担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

Background/Objectives: The OTOF gene is reported to be the causative gene for non-syndromic recessive sensorineural hearing loss and auditory neuropathy spectrum disorder. About 300 variants have been reported, but there have been no reports to date on copy gain variants. Methods: We identified a copy gain variant in the OTOF gene through short-read next-generation sequencing analysis from one patient with auditory neuropathy. We also performed long-read next-generation sequencing analysis using the Oxford Nanopore Technologies adaptive sampling procedure. Results: The four-year-old male carried a duplication of chr2: 26,477,852 to 26,483,106 (a 5254-base duplication including exon 14 to exon 18 of the OTOF gene NM_001287489) and a c.5385C>A single nucleotide variant. We also confirmed that these two variants were located in the trans configuration based on haplotype phasing results using the long-read next-generation sequencing data. Conclusions: This is the first report of an auditory neuropathy patient with a large duplication variant in the OTOF gene. The identified variants were novel, but based on the clinical phenotype of the patient, these variants seem to be the genetic cause of this patient’s phenotype. Oxford Nanopore Technologies adaptive sampling is a powerful tool for the analysis of structural variants (particularly for determining the breakpoint and direction) and haplotype phasing.

DOI： 10.3390/genes16020116

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.7759/cureus.76342

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掲載種別：研究論文（学術雑誌）  

The MYO7A gene is known to be responsible for both syndromic hearing loss (Usher syndrome type1B:USH1B) and non-syndromic hearing loss including autosomal dominant and autosomal recessive inheritance (DFNA11, DFNB2). However, the prevalence and detailed clinical features of MYO7A-associated hearing loss across a large population remain unclear. In this study, we conducted next-generation sequencing analysis for a large cohort of 10,042 Japanese hearing loss patients. As a result, 137 patients were identified with MYO7A-associated hearing loss so that the prevalence among Japanese hearing loss patients was 1.36%. We identified 70 disease-causing candidate variants in this study, with 36 of them being novel variants. All variants identified in autosomal dominant cases were missense or in-frame deletion variants. Among the autosomal recessive cases, all patients had at least one missense variant. On the other hand, in patients with Usher syndrome, almost half of the patients carried biallelic null variants (nonsense, splicing, and frameshift variants). Most of the autosomal dominant cases showed late-onset progressive hearing loss. On the other hand, cases with autosomal recessive inheritance or Usher syndrome showed congenital or early-onset hearing loss. The visual symptoms in the Usher syndrome cases developed between age 5–15, and the condition was diagnosed at about 6–15 years of age.

DOI： 10.1038/s41598-024-57415-1

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Association for Cancer Research (AACR)  

Abstract

Adoptive cell therapy (ACT) using retrovirally transduced T cells represents a promising strategy for enhancing antitumor responses. When used with TriVax, a peptide vaccination strategy, this approach synergistically expands antigen-specific cell populations. STAT5 plays a vital role as a transcription factor in regulating T-cell proliferation and their differentiation into effector and memory T cells. We aimed to explore the combination therapy using CD8 T cells engineered to express constitutively active STAT5 (CA-STAT5) with vaccines. CD8 T cells were transduced with a retrovirus (RV) encoding the mouse gp100 T-cell receptor (TCR). In certain treatment groups, cells were also co-transduced with RV encoding CA-STAT5. We assessed transduction efficiency and functional activity through flow cytometry and various functional assays. B16F10 tumor-bearing mice were treated with ACT using RV-transduced CD8 T cells and subsequently vaccinated with TriVax. We demonstrate that TriVax selectively enhanced the expansion of ACT cell populations bearing gp100-specific TCRs. T cells engineered to express CA-STAT5 showed not only increased expansion and polyfunctionality but also reduced PD-1 expression, leading to decreased cellular exhaustion. In a B16F10 melanoma mouse model, our approach yielded a potent antitumor effect, with CA-STAT5 further amplifying this response. We found that CA-STAT5 improved antitumor activities, in part, by attenuating the PD-1/PD-L1 inhibitory pathway. These findings indicate that TCR-transduced CD8 T cells can undergo antigen-dependent expansion when exposed to TriVax. Additionally, the expression of CA-STAT5 enhances T-cell proliferation and persistence, partly by promoting resistance to PD-1/PD-L1–mediated inhibition in antitumor T cells.

DOI： 10.1158/1535-7163.mct-24-0505

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その他リンク： https://aacrjournals.org/mct/article-pdf/doi/10.1158/1535-7163.MCT-24-0505/3525091/mct-24-0505.pdf

記述言語：日本語   出版者・発行元：(一社)日本耳科学会  

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3950/jibiinkotokeibu.127.9_971

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Predictive biomarkers for nivolumab in recurrent or metastatic head and neck squamous cell carcinoma (RMHNSCC) have not yet been established. METHODS: The tumor proportion score (TPS), combined positive score (CPS), and soluble forms of programmed cell death ligand-1 (PD-L1) and programmed cell death ligand-2 (PD-L2) were retrospectively analyzed in patients with RMHNSCC treated with nivolumab. RESULTS: The positivity rates for TPS (PD-L1), CPS (PD-L1), TPS (PD-L2), and CPS (PD-L2) were 73.8%, 78.2%, 56.4%, and 78.2%, respectively. Patients with high TPS (PD-L1), CPS (PD-L1), or CPS (PD-L1 and PD-L2) showed significantly prolonged progression-free survival. Favorable overall survival was associated with high CPS (PD-L1 and PD-L2) and low soluble PD-L1 and PD-L2 levels. The expressions of tissue and soluble PD-L1/2 were not correlated. CONCLUSIONS: Our study revealed that compared to PD-L1 expression alone, dual expression of PD-L1 and PD-L2 in tissue or soluble form could be feasible biomarkers in patients with RMHNSCC who received nivolumab.

DOI： 10.1002/hed.27787

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担当区分：筆頭著者,　最終著者,　責任著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

DOI： 10.24805/jiaio.4.3_123

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

Intratumoral hypoxia is associated with tumor progression, aggressiveness, and therapeutic resistance in several cancers. Hypoxia causes cancer cells to experience replication stress, thereby activating DNA damage and repair pathways. MutT homologue-1 (MTH1, also known as NUDT1), a member of the Nudix family, maintains the genomic integrity and viability of tumor cells in the hypoxic tumor microenvironment. Although hypoxia is associated with poor prognosis and can cause therapeutic resistance by regulating the microenvironment, it has not been considered a treatable target in cancer. This study aimed to investigate whether hypoxia-induced MTH1 is a useful target for immunotherapy and whether hypoxic conditions influence the antitumor activity of immune cells. Our results showed that MTH1 expression was elevated under hypoxic conditions in head and neck cancer cell lines. Furthermore, we identified a novel MTH1-targeting epitope peptide that can activate peptide-specific CD4+ helper T cells with cytotoxic activity. The proliferation and cytotoxic activity of T cells were maintained under hypoxic conditions, and PD-1 blockade further augmented the cytotoxicity. These results indicate that MTH1-targeted immunotherapy combined with checkpoint blockade can be an effective strategy for the treatment of hypoxic tumors.

DOI： 10.3390/cancers16173013

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.7759/cureus.66665

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The identification of epitope peptides from tumor-associated antigens (TAAs) is informative for developing tumor-specific immunotherapy. However, only a few epitopes have been detected in mouse TAAs of head and neck cancer (HNSCC). METHODS: Novel mouse c-Met-derived T-cell epitopes were predicted by computer-based algorithms. Mouse HNSCC cell line-bearing mice were treated with a c-Met peptide vaccine. The effects of CD8 and/or CD4 T-cell depletion, and vaccine combination with immune checkpoint inhibitors (ICIs) were evaluated. Tumor re-inoculation was performed to assess T-cell memory. RESULTS: We identified c-Met-derived short and long epitopes that elicited c-Met-reactive antitumor CD8 and/or CD4 T-cell responses. Vaccination using these peptides showed remarkable antitumor responses via T cells in which ICIs were not required. The c-Met peptide-vaccinated mice rejected the re-inoculated tumors. CONCLUSIONS: We demonstrated that novel c-Met peptide vaccines can induce antitumor T-cell response, and could be a potent immunotherapy in a syngeneic mouse HNSCC model.

DOI： 10.1002/hed.27703

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記述言語：日本語   出版者・発行元：日本口腔・咽頭科学会  

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記述言語：日本語   出版者・発行元：日本口腔・咽頭科学会  

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記述言語：日本語   出版者・発行元：一般社団法人 日本がん看護学会  

DOI： 10.18906/jjscn.38_95_nonaka

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Fluorine 18-fluoro-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) is commonly used for the staging of head and neck cancer. This study aimed to evaluate the correlation between 18F-FDG PET/CT, haematological parameters and prognosis in patients with advanced head and neck cancer. METHODS: This was a single-institutional retrospective study of 83 patients with advanced head and neck squamous cell carcinoma (HNSCC) who underwent 18F-FDG PET/CT imaging before initial treatment between 2014 and 2018. 18F-FDG PET/CT after treatment was performed in 57 patients. The prognostic parameters of the pre- and post-treatment maximum standardised uptake value (SUVmax), metabolic tumour volume (MTV), total lesion glycolysis (TLG) of primary tumours and haematological parameters were analysed to evaluate the association between overall survival (OS) and progression-free survival (PFS). RESULTS: Pre-MTV, pre-TLG and post-SUVmax were significantly associated with poor OS and PFS (p < 0.05). Haematological parameters, including pretreatment neutrophil/lymphocyte ratio and C-reactive protein/albumin ratio, were associated with 18F-FDG PET/CT parameters. In multivariate analysis, post-SUVmax was an independent prognostic factor for OS and PFS. CONCLUSION: A correlation between PET/CT metabolic and haematological parameters was observed. The volume and intensity of 18F-FDG uptake region, in addition to haematological parameters, are feasible markers for predicting the progression of HNSCC in daily practice. Further, post-SUVmax could be an independent parameter for predicting poor survival.

DOI： 10.1111/coa.14195

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Tonsillectomy with steroid pulse therapy (TSP) and tonsillectomy monotherapy (T) have improved the prognosis of patients with immunoglobulin A nephropathy (IgAN). However, a consensus has not been reached on the best treatment for these patients. This study aimed to compare the efficacies of TSP and T. METHODS: Data of patients with IgAN who received TSP or T were retrospectively analyzed. The exclusion criterion was a serum creatinine level > 1.5 mg/dL. The clinical remission and renal survival rates were compared. RESULTS: Patients were divided into groups based on the treatment method: the TSP (n = 82) and T groups (n = 41). No significant differences were observed in patient characteristics, except for the observation period (TSP: 60 months, T: 113 months). The log-rank test revealed that the clinical remission rate was significantly higher in the TSP group than in the T group (p < 0.05). The superiority of TSP was also observed in the urinary protein excretion (> / = or < 1 g/day) of the two subgroups. According to the Cox proportional-hazards model, the treatment method and daily urinary protein extraction were independent factors affecting clinical remission. The 10-year renal survival rates in the TSP and T groups were 100% and 92.5%, respectively. The log-rank test revealed a tendency for a higher renal survival rate in the TSP group than in the T group (p = 0.09). CONCLUSION: The clinical remission rate was significantly higher with TSP than with T, regardless of urinary protein levels. TSP tended to have a better renal survival rate than T.

DOI： 10.1007/s10157-024-02527-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

In CD70-expressing tumors, the interaction of CD70 on tumor cells with its lymphocyte receptor, CD27, is thought to play a role in immunosuppression in the tumor microenvironment and elevated serum levels of soluble CD27 (sCD27). Previous studies showed that CD70 is expressed in nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-related malignancy. However, the association between intratumoral CD70/CD27 expression and serum levels of sCD27 in NPC remains unclear. In the present study, we show that CD70 is primarily expressed by tumor cells in NPC and that CD27-positive lymphocytes infiltrate around tumor cells. NPC patients with CD27-positive lymphocytes had significantly better prognosis than patients lacking these cells. In addition, high CD70 expression by tumor cells tended to be correlated with shorter survival in NPC patients with CD27-positive lymphocytes. Serum sCD27 levels were significantly increased in patients with NPC and provided good diagnostic accuracy for discriminating patients from healthy individuals. The concentration of serum sCD27 in patients with CD70-positive NPC with CD27-positive lymphocytes was significantly higher than in patients with tumors negative for CD70 and/or CD27, indicating that the intratumoral CD70/CD27 interaction boosts the release of sCD27. Furthermore, positive expression of CD70 by NPC cells was significantly correlated with EBV infection. Our results suggest that CD70/CD27-targeted immunotherapies may be promising treatment options and that sCD27 may become an essential tool for evaluating the applicability of these therapies by predicting the intratumoral CD70/CD27 interaction in NPC.

DOI： 10.1111/cas.16079

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Head and neck squamous cell carcinoma (HNSCC) has a poor prognosis. Each year, approximately 880,000 patients are newly diagnosed with HNSCC worldwide, and 450,000 patients with HNSCC die. Risk factors for developing HNSCC have been identified, with cigarette smoking, alcohol consumption, and viral infections being the major factors. Owing to the prevalence of human papillomavirus infection, the number of HNSCC cases is increasing considerably. Surgery and chemoradiotherapy are the primary treatments for HNSCC. With advancements in tumor biology, patients are eligible for novel treatment modalities, namely targeted therapies, immunotherapy, and photoimmunotherapy. Because this area of research has rapidly progressed, clinicians should understand the basic biology of HNSCC to choose an appropriate therapy in the upcoming era of personalized medicine. This review summarized recent developments in tumor biology, focusing on epidemiology, genetic/epigenetic factors, the tumor microenvironment, microbiota, immunity, and photoimmunotherapy in HNSCC, as well as how these findings can be translated into clinical settings.

DOI： 10.1016/j.anl.2023.08.006

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Salivary gland cancer (SGC) is rare and comprises over 20 histological subtypes. Recently, clinical experience regarding immunotherapies for SGCs has been accumulating, yet their efficacy remains controversial. Understanding the tumor microenvironment (TME), including the expression of immune checkpoint molecules in SGC, is crucial to optimizing immunotherapy. In this review, we demonstrate that high-grade mucoepidermoid carcinoma and salivary duct carcinoma generally exhibit immune-hot TME with high immune cell infiltration, frequent genetic mutations, and robust immune checkpoint molecule expression. In contrast, adenoid cystic carcinomas exhibit an immune-cold TME. While the reported efficacy of immune checkpoint inhibitors (ICIs) for SGCs is generally poor, several studies showed promising clinical efficacy of ICIs, with an objective response rate ranging from 20.0-33.3%, indicating that ICIs might be beneficial for a specific population of SGC. Molecule-targeted therapies including anti-human epidermal growth factor receptor 2 and anti-androgen receptor therapies have shown promising clinical efficacy against SGC. Recent evidence indicates that these molecules could be targets for antigen-specific immunotherapies including chimeric antigen receptor-T therapy and cancer vaccines. This review discusses the current understanding and future directions of immunotherapies for SGCs, including ongoing clinical trials.

DOI： 10.3390/cancers16061205

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担当区分：責任著者   記述言語：英語  

Lipomas are among the most common soft tissue tumors. Surgical removal of lipoma is considered if the patient has symptoms or cosmetic challenges. Lipomas that develop from any fat tissue in the body and involve the eustachian tube are extremely rare. Herein, we report the case of a patient with a lipoma arising in the eustachian tube. We also summarized the literature on tumors originating from the eustachian tubes. A 62-year-old female presented to our department with a five-year history of left nasal congestion. Nasal endoscopy revealed a tumor in the left eustachian tube. The tumor was considered a lipoma on computed tomography (CT) and magnetic resonance imaging (MRI) and was removed using a transnasal endoscopic approach. Nasal endoscopy and radiologic imaging can be used to detect tumors in the nasopharynx, including the eustachian tubes. Magnetic resonance imaging is particularly useful for the diagnosis of lipomas. A lipoma in the eustachian tube can cause nasal congestion and aural fullness, and the transnasal endoscopic approach is useful for tumor removal.

DOI： 10.7759/cureus.56597

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記述言語：日本語   出版者・発行元：日本耳鼻咽喉科免疫アレルギー感染症学会  

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記述言語：日本語   出版者・発行元：日本耳鼻咽喉科免疫アレルギー感染症学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chronic rhinosinusitis (CRS) is a persistent inflammatory disease of the nasal cavity and paranasal sinuses. Traditional classification is denoted by the presence (CRSwNP) or absence of nasal polyps (CRSsNP). Particularly, CRSwNP is distinguished by the presence of infiltrating cells and inflammatory markers in the nasal mucosa. Patients with CRSwNP in Western countries predominantly display a type 2 endotype, whereas those in Asian regions display a mixed type 2 endotype. Nevertheless, recent transcriptome analyses have revealed two types of nasal polyps - type 2 and non-type 2 polyps, suggesting that geographical differences in endotypes likely resulted from the different proportions of each endotype. Moreover, various endotypes of CRSsNP have been identified, making phenotype a crucial factor for predicting treatment efficacy. Type 2 endotypes, designated as eosinophilic CRS (ECRS) in Japan, are characterized by severe eosinophilic infiltration into the paranasal sinus tissue and are particularly refractory. In this review, we discuss the latest developments in ECRS. We also provide recent findings on the involvement of nasal epithelial cells in pathogenesis.

DOI： 10.1016/j.anl.2023.08.002

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Immunoglobulin G4-related disease (IgG4-RD) is a systemic inflammatory disease characterized by elevated serum IgG4, tissue infiltration of IgG4-positive cells, and fibrosis. Although a number of IgG4-RD patients show sinonasal involvement, there is little known about sinonasal inflammation associated with IgG4-RD. This study aimed to describe the clinicopathological features of sinonasal inflammation associated with IgG4-RD and to compare with other inflammatory diseases, such as eosinophilic chronic rhinosinusitis (ECRS) and granulomatosis with polyangiitis (GPA). METHODS: A retrospective analysis of clinicopathological features of patients with sinonasal lesions and high serum IgG4 was performed. Patient data were reviewed to determine whether they fulfilled the diagnostic criteria for other inflammatory diseases. RESULTS: Six of 7 patients were diagnosed with IgG4-RD, while 1 patient was diagnosed with GPA. In the 6 patients with IgG4-RD, intranasal findings showed nasal polyps in 3 patients (50%) and nasal crusting in the 3 patients (50%). Computed tomography showed ethmoid sinus involvement in 5 patients (83%). Five of the 6 patients (83%) were diagnosed with IgG4-RD based on nasal biopsy, whereas 1 patient (17%) was diagnosed based on lacrimal gland biopsy. Four patients fulfilled the Japanese epidemiological survey of refractory ECRS (JESREC) criteria. However, none of the patients showed eosinophil infiltration. Although the patient with GPA showed high levels of serum IgG4 and tissue infiltration of IgG4-positive cells in the nasal biopsy, the patient showed common clinical features of GPA. CONCLUSION: Patients with sinonasal inflammation associated with IgG4-RD had similar clinical characteristics with ECRS and GPA. Histopathological findings of the nasal biopsy from clinically diagnosed GPA was consistent with that of IgG4-RD. Sinonasal inflammation associated with IgG4-RD should be diagnosed based not only on tissue infiltration of IgG4-positive cells but in conjunction with clinical findings such as local nasal characteristics, involvement of other organs, and serum antineutrophil cytoplasmic antibody levels. IgG4-RD should be ruled out in patients with eosinophilia without histopathological eosinophil infiltration.

DOI： 10.1159/000538365

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記述言語：日本語   出版者・発行元：特定非営利活動法人 日本頭頸部外科学会  

【はじめに】Marine-Lenhart症候群は，Basedow病とPlummer病の2つの異なる病態が併存する疾患である。今回われわれは，甲状腺腫瘍の経過観察中に甲状腺機能亢進症を指摘され，各画像所見からMarine-Lenhart症候群の診断となった1例を経験したので，若干の文献的考察を加えて報告する。
<br>【症例】69歳女性。20年以上前に左甲状腺腫瘍の指摘があったが，細胞診で良性の結果で経過観察となっていた。健康診断で甲状腺機能亢進を指摘され，近医耳鼻咽喉科を受診。エコーで左葉に結節を認め，free T3およびfree T4が高値だったため，Plummer病の疑いで精査加療目的に当科紹介初診となった。当院での採血でTRAbが陽性であり，CTやエコーでは甲状腺左葉に最大径32mmの充実性腫瘤を認めた。同腫瘤の穿刺吸引細胞診では悪性所見は認めなかった。I¹²³シンチグラフィーでは甲状腺左葉腫瘍に集積を認め，それ以外の甲状腺実質にも淡い集積を認めた。以上からMarine-Lenhart症候群と診断し，甲状腺全摘術を施行した。

DOI： 10.5106/jjshns.34.99

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：耳鼻咽喉科臨床学会  

DOI： 10.5631/jibirin.117.233

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その他リンク： https://ndlsearch.ndl.go.jp/books/R000000004-I033365984

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：耳鼻咽喉科臨床学会  

DOI： 10.5631/jibirin.117.647

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その他リンク： https://ndlsearch.ndl.go.jp/books/R000000004-I033616512

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Due to the rarity and various histological types, a standard chemotherapy regimen for recurrent or metastatic salivary gland carcinoma (SGC) has not been established. Molecular-targeted therapy is a novel cancer therapy based on the expression of target molecules. However, few molecular-targeted therapy types have shown satisfactory efficacy for patients with SGC. Our study described promising results of epidermal growth factor receptor (EGFR)-targeting therapy with paclitaxel in patients with SGC. METHODS: The medical records of patients with recurrent SGC treated with weekly cetuximab combined with paclitaxel (Cmab-PTX) between December 2017 and December 2022 at our institutions were retrospectively analyzed. RESULTS: Seven patients with SGC received Cmab-PTX therapy. The median age was 76 years. All patients were high-grade histological types, and EGFR expression was positive in all examined patients. Cmab-PTX was administered for a median period of 20 months (range of 2-36 months). The overall responses were three with complete response, two with partial response, one with stable disease (&gt;24 weeks), and one with progressive disease. The objective response and disease control rates were 71.4% and 85.7%, respectively. Progression-free survival ranged between 2 and 36 months (median 12 months), whereas overall survival ranged between 4 and 111 months (median 36 months). One patient experienced a grade 4 adverse event (neutropenia), which was conservatively manageable. CONCLUSION: Although the treatment sensitivity of SGC with high-grade histological types is usually poor, Cmab-PTX could be a promising treatment regimen for recurrent SGC. Due to the rarity and various histological types, a standard chemotherapy regimen for recurrent or metastatic salivary gland carcinoma (SGC) has not been established. Molecular-targeted therapy is a novel cancer therapy based on the expression of target molecules. However, few molecular-targeted therapy types have shown satisfactory efficacy in patients with SGC. Our study described promising results of cetuximab (Cmab), epidermal growth factor receptor (EGFR)-targeting therapy with paclitaxel (PTX) in patients with SGC. Seven patients with SGC received Cmab-PTX therapy. The median age was 76 years. All patients were high-grade histological types, and EGFR expression was positive in all examined patients. Cmab-PTX was administered for a median period of 20 months. The overall responses were three with complete response, two with partial response, one with stable disease (&gt;24 weeks), and one with progressive disease. The objective response rate was 71.4%. Progression-free survival ranged between 2 and 36 months (median 12 months), whereas overall survival ranged between 4 and 111 months (median 36 months). One patient experienced a grade 4 adverse event (neutropenia), which was conservatively manageable. Our study revealed a preferable objective response rate of Cmab-PTX for patients with high-grade SGC. Although the treatment sensitivity of SGC with high-grade histological types is usually poor, Cmab-PTX could be a promising treatment regimen for recurrent SGC.

DOI： 10.1159/000534516

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The incidence of thyroid cancer (TC) has increased over the past 30 years. Although differentiated thyroid cancer (DTC) has a good prognosis in most patients undergoing total thyroidectomy followed by radioiodine therapy (RAI), 5-10% of patients develop metastasis. Anaplastic thyroid cancer (ATC) has a low survival rate and few effective treatments have been available to date. Recently, tyrosine kinase inhibitors (TKIs) have been successfully applied to RAI-resistant or non-responsive TC to suppress the disease. However, TC eventually develops resistance to TKIs. Immunotherapy is a promising treatment for TC, the majority of which is considered an immune-hot malignancy. Immune suppression by TC cells and immune-suppressing cells, including tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, is complex and dynamic. Negative immune checkpoints, cytokines, vascular endothelial growth factors (VEGF), and indoleamine 2,3-dioxygenase 1 (IDO1) suppress antitumor T cells. Basic and translational advances in immune checkpoint inhibitors (ICIs), molecule-targeted therapy, tumor-specific immunotherapy, and their combinations have enabled us to overcome immune suppression and activate antitumor immune cells. This review summarizes current findings regarding the immune microenvironment, immunosuppression, immunological targets, and immunotherapy for TC and highlights the potential efficacy of immunotherapy.

DOI： 10.3390/vaccines12010045

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND Malignant lymphomas can occur at various sites. Hypopharyngeal tumors are at risk for airway obstruction and require rapid diagnosis and treatment. Most hypopharyngeal malignancies are squamous cell carcinomas; other tumors are rare. To date, only a few cases of malignant hypopharyngeal lymphoma have been reported, and its specific characteristics are unknown. Herein, we report a case of right hypopharyngeal diffuse large B-cell lymphoma (DLBCL) in a 74-year-old man with dysphagia. CASE REPORT A 74-year-old man presented to our hospital with dysphagia. He had no relevant medical history. Endoscopic examination revealed a right hypopharyngeal tumor. The surface of the tumor was smooth, with no evidence of hemorrhage. Computed tomography revealed a 40-mm mass located in the hypopharynx. We performed a tracheotomy and biopsy of the tumor. Histopathological examination revealed a diffuse proliferation of large atypical B cells with negative staining for Epstein-Barr virus by in situ hybridization. Immunohistochemical staining was positive for CD20 but negative for CD3 and CD10. The patient was administered chemotherapy. The tumor reduced in size, and the patient recovered completely. During the two-year follow up, no recurrence of cancer was observed. CONCLUSIONS Although most hypopharyngeal tumors are squamous cell carcinomas (SCCs), the possibility of other types of tumors should also be considered. Malignant lymphoma of the hypopharynx is rare, and more cases need to be studied and reported in the future.

DOI： 10.12659/AJCR.942070

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/emp2.13082

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担当区分：責任著者   記述言語：英語  

DOI： 10.1007/s13760-023-02181-6

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 69-year-old man with impaired consciousness, right hemiplegia, and aphasia was admitted to our emergency room for thorough examination. Magnetic resonance imaging (MRI) and 3-dimensional computed tomography (3D CT) scan of the head revealed a cerebral infarction due to dissection of the left internal carotid artery. Contrast-enhanced CT prior to internal carotid artery stenting showed that the left elongated styloid process ran in close proximity to the left internal carotid artery, with a minimum distance of 2 mm. The patient underwent stenting at the internal carotid artery 16 days after disease onset. The patient was referred to our department for left elongated styloid process resection to reduce the risk of further internal carotid artery injury. Resection of the left styloid process through a cervical incision was performed. Six months after surgery, there was no recurrence of the internal carotid artery dissection.

DOI： 10.1016/j.anl.2023.01.011

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/emp2.13087

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担当区分：責任著者   記述言語：英語  

Immune checkpoint inhibitors (ICIs) are a novel treatment option for treating head and neck squamous cell carcinoma (HNSCC). Among the immune-related adverse effects, cerebral infarction (CI) is a rare but fatal complication, and it has been reported in various cancers, except HNSCC. Herein, we describe three cases of patients diagnosed with HNSCC who experienced CI following ICI treatment. In addition, we conducted a comprehensive literature review on ICI-related thrombosis. Three patients with recurrent HNSCC were treated with nivolumab. Two patients had a history of CI, or heart disease, and were concurrently prescribed antithrombotic medications during nivolumab treatment. The number of nivolumab administrations varied from 1-25 before the onset of CI. All patients experienced worsening of neurological symptoms due to CI, irrespective of antithrombotic treatment, and they ultimately succumbed to the disease within 16-222 days following their initial ICI administration. ICIs may cause thromboembolisms, leading to CI. Based on our review of the literature, a history of thromboembolism or heart disease could be a risk factor for ICI-related thrombosis.

DOI： 10.7759/cureus.47406

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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担当区分：筆頭著者,　責任著者   記述言語：英語  

Upper airway infections caused by anaerobic bacteria, including pharyngitis and tonsillitis, are a common cause of septic thrombosis (Lemierre's syndrome). Although otitis media rarely progresses to systemic infection, an abscess surrounding the middle ear can affect the central nervous system. Trueperella bernardiae was originally considered a non-pathogenic aerobic bacterium but has subsequently been reported to cause bacteremia and brain abscesses. Here, we report a case of otitis media caused by T. bernardiae complicated by meningitis, subdural empyema, and septic pulmonary emboli in an immunocompetent patient.

DOI： 10.7759/cureus.42977

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Brachyury is a transcription factor belonging to the T-box gene family and is involved in the posterior formation of the mesoderm and differentiation of chordates. As the overexpression of Brachyury is a poor prognostic factor in a variety of cancers, the establishment of Brachyury-targeted therapy would be beneficial for the treatment of aggressive tumors. Because transcription factors are difficult to treat with a therapeutic antibody, peptide vaccines are a feasible approach for targeting Brachyury. In this study, we identified Brachyury-derived epitopes that elicit antigen-specific and tumor-reactive CD4+ T cells that directly kill tumors. T cells recognizing Brachyury epitopes were present in patients with head and neck squamous cell carcinoma. Next, we focused on gemcitabine (GEM) as an immunoadjuvant to augment the efficacy of antitumor responses by T cells. Interestingly, GEM upregulated HLA class I and HLA-DR expression in tumor, followed by the upregulation of anti-tumor T cell responses. As tumoral PD-L1 expression was also augmented by GEM, PD-1/PD-L1 blockade and GEM synergistically enhanced the tumor-reactivity of Brachyury-reactive T cells. The synergy between the PD-1/PD-L1 blockade and GEM was also confirmed in a mouse model of head and neck squamous cell carcinoma. These results suggest that the combined treatment of Brachyury peptide with GEM and immune checkpoint blockade could be a promising immunotherapy against head and neck cancer.

DOI： 10.1007/s00262-023-03460-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A 15-year-old girl presented with a 3-year-history of continuous outflow of saliva from a pharyngocutaneous fistula, located at 5 mm superior to her tracheal stoma. She was diagnosed with Miller-Dieker syndrome at birth. At 2 years of age, pediatric surgeons at our institution carried out laryngotracheal separation to prevent aspiration pneumonia. At the age of 12 years, she developed continuous saliva discharge from the fistula. We performed central-part laryngectomy and resection of the pharyngocutaneous fistula, which relieved her from the continuous saliva discharge. Central-part laryngectomy is less invasive and easier to perform than total laryngectomy. We hereby present a case and retrospective analysis of 12 patients, who underwent central-part laryngectomy.

DOI： 10.1016/j.anl.2022.04.011

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記述言語：日本語   出版者・発行元：日本口腔・咽頭科学会  

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記述言語：日本語   出版者・発行元：日本口腔・咽頭科学会  

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記述言語：日本語   出版者・発行元：日本口腔・咽頭科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The engagement of CD27 on lymphocytes with its ligand, CD70, on tumors is believed to mediate tumor immune evasion and the elevation of serum soluble CD27 (sCD27) levels in patients with CD70-positive malignancies. We previously showed that CD70 is expressed in extranodal natural killer/T-cell lymphoma, nasal type (ENKL), an Epstein-Barr virus (EBV)-related malignancy. However, little is known about serum sCD27 expression and its association with the clinical characteristics of, and the CD27/CD70 interaction in, ENKL. In the present study, we show that serum sCD27 is significantly elevated in the sera of patients with ENKL. The levels of serum sCD27 provided excellent diagnostic accuracy for discriminating patients with ENKL from healthy subjects, correlated positively with the levels of other diagnostic markers (lactate dehydrogenase, soluble interleukin-2 receptor, and EBV-DNA), and decreased significantly following treatment. Elevated serum sCD27 levels also correlated significantly with advanced clinical stage and tended to correspond with shorter survival, in patients with ENKL. Immunohistochemistry indicated that CD27-positive tumor-infiltrating immune cells exist adjacent to CD70-positive lymphoma cells. In addition, serum sCD27 levels in patients with CD70-positive ENKL were significantly higher than those in patients with CD70-negative ENKL, suggesting that the intra-tumoral CD27/CD70 interaction boosts the release of sCD27 in serum. Furthermore, the EBV-encoded oncoprotein latent membrane protein 1 upregulated CD70 expression in ENKL cells. Our results suggest that sCD27 may serve as a novel diagnostic biomarker and also may serve as a tool for evaluating the applicability of CD27/CD70-targeted therapies by predicting intra-tumoral CD70 expression and CD27/CD70 interaction in ENKL.

DOI： 10.1007/s00262-023-03394-7

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   出版者・発行元：(一社)日本頭頸部癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本頭頸部癌学会  

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記述言語：日本語   出版者・発行元：(一社)日本耳鼻咽喉科頭頸部外科学会  

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記述言語：日本語   出版者・発行元：日本耳鼻咽喉科免疫アレルギー感染症学会  

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記述言語：日本語   出版者・発行元：日本耳鼻咽喉科免疫アレルギー感染症学会  

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記述言語：日本語   出版者・発行元：日本耳鼻咽喉科免疫アレルギー感染症学会  

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：一般社団法人 日本耳鼻咽喉科頭頸部外科学会  

免疫療法は癌治療において手術, 抗癌剤, 放射線療法に次ぐ第4の柱として確立された. 現状で用いられている免疫療法は, 腫瘍や腫瘍微小環境において抗腫瘍免疫を抑制する負の免疫チェックポイント分子への阻害抗体であり, PD-1 / PD-L1 や CTLA-4 がその代表的な分子として挙げられる. これらの分子に対する中和抗体は抗原性が高い悪性腫瘍として知られる悪性黒色腫で臨床応用が開始され, 一定の臨床効果を示した. 頭頸部癌も比較的抗原性が高い腫瘍として知られており, 2017年に Nivolumab, 2019年には Pembrolizumab の臨床応用が開始された. 臨床応用から数年が経過し, 免疫療法はリアルワールドで2割前後の奏効率を示している. 免疫チェックポイント阻害薬の使用に対するハードルは下がり, 全国で多くの耳鼻咽喉科・頭頸部外科医が免疫療法に携わっている. そのため, 臨床医にとっても頭頸部癌における腫瘍免疫の詳細な理解が求められるようになってきた. 本稿では, 頭頸部癌を中心とした増殖・転移に関するメカニズムおよび腫瘍免疫を応用した治療法の現状と未来について概説する.

DOI： 10.3950/jibiinkotokeibu.126.2_81

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その他リンク： https://ndlsearch.ndl.go.jp/books/R000000004-I032702551

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Homeobox B7 (HOXB7) is a master regulatory gene that regulates cell proliferation and activates oncogenic pathways. Overexpression of HOXB7 correlates with aggressive behavior and poor prognosis in patients with cancer. However, the expression and role of HOXB7 in head and neck squamous cell carcinoma (HNSCC) remain unclear. In this study, we observed that most samples from patients with oropharyngeal cancer and HNSCC expressed HOXB7. As no direct inhibitor has been reported, we identified a potent peptide epitope to target HOXB7-expressing tumors through immune cells. A novel HOXB7-derived peptide epitope (HOXB78-25 ) elicited antigen-specific and tumor-reactive promiscuous CD4+ T cell responses. These CD4+ T cells produced γ-interferon (IFN-γ) and had the direct ability to kill tumors through granzyme B. Notably, downregulation of HOXB7 using siRNA enhanced human leukocyte antigen class II expression on tumor cells by decreasing the phosphorylation of MAPK. Mitogen-activated protein kinase inhibition augmented IFN-γ production by HOXB7-reactive CD4+ T cell responses without decreasing the expression of HOXB7. These results suggest that combining HOXB7 peptide-based vaccine with MAPK inhibitors could be an effective immunological strategy for cancer treatment.

DOI： 10.1111/cas.15619

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：耳鼻咽喉科臨床学会  

DOI： 10.5631/jibirin.116.45

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その他リンク： https://ndlsearch.ndl.go.jp/books/R000000004-I032613586

記述言語：日本語   出版者・発行元：日本口腔・咽頭科学会  

PFAPA症候群は自己炎症性疾患の一つであり，周期性発熱，アフタ性口内炎，頸部リンパ節炎，咽頭炎を主症状とし5歳以下の乳幼児に発症する．初期治療として薬物投与などが行われるが，効果が不十分な場合は口蓋扁桃摘出術の適応となる．今回我々は，口蓋扁桃摘出術を行なったPFAPA症候群の5例を経験したので考察を加え報告する．
<br>対象は当科で口蓋扁桃摘出術を行ったPFAPA症候群5例である． 男児4例，女児1例であり，発症年齢は0-5歳（中央値3歳），口蓋扁桃摘出術時の年齢は2-7歳（中央値5歳）であった． 症状としては周期性発熱5例，アフタ性口内炎1例，頸部リンパ節炎2例，咽頭炎5例を認めた． 術後は全例に周期性発熱の消失または発熱周期の延長を認めた． 口蓋扁桃摘出術はPFAPA症候群における症状改善に効果が高く，薬物療法に抵抗する症例において，小児科担当医師や患児，両親の意見も踏まえ，扁桃摘出術を勧めるべきである．

DOI： 10.14821/stomatopharyngology.36.102

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掲載種別：研究論文（学術雑誌）  

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：日本鼻科学会  

DOI： 10.7248/jjrhi.62.269

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

There have been very few reports of thyroid metastasis from cervical carcinoma. This article reports a case of metastasis from cervical carcinoma. A 69-year-old woman with a history of cervical cancer presented to our department with right cervical swelling. She had suffered from paralysis of the left recurrent laryngeal nerve after undergoing left hemithyroidectomy 16 years ago. Computed Tomography (CT) and magnetic resonance imaging scans revealed a right thyroid tumor with bilateral enlargement of the cervical lymph nodes. Fluorodeoxyglucose positron emission tomography/CT imaging revealed high uptake in the right thyroid tumor, cervical lymph nodes, and right iliac bone. Fine-needle aspiration cytology revealed atypical epithelial cells with a high nuclear/cell ratio and hyperchromatic nuclei, which resembled cervical cancer cells. Given the risk of airway obstruction and dysphagia, the patient underwent tracheostomy, right hemithyroidectomy, and neck dissection for preserving the quality of life. Pathological examination revealed normal thyroid tissue with p16-positive atypical epithelial cells, which suggested thyroid metastasis from the cervical cancer. The patient has remained alive without any symptoms for 5 postoperative months.

DOI： 10.1016/j.bjorl.2023.03.005

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：耳鼻咽喉科臨床学会  

DOI： 10.5631/jibirin.116.25

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その他リンク： https://ndlsearch.ndl.go.jp/books/R000000004-I032613572

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：耳鼻咽喉科臨床学会  

DOI： 10.5631/jibirin.116.161

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その他リンク： https://ndlsearch.ndl.go.jp/books/R000000004-I032678749

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To evaluate the efficacy and safety of Alternating Chemoradiotherapy (ACRT) using cisplatin and 5-Fluorouracil (5-FU) in patients with nasopharyngeal carcinoma. METHODS: This was a retrospective study in which patients' clinical records were reviewed to identify patients with a new diagnosis of nasopharyngeal carcinoma at our institution between January 2005 and January 2019. Thirty-seven eligible patients were identified; of these, the clinical details of 27 patients treated with ACRT were evaluated. Patient outcomes, including overall survival and progression-free survival, and adverse events were assessed. RESULTS: Of these initial 37 patients, 1, 10, 13, 10, and 3 were staged as I, II, III, IVA, and IVB, respectively, as defined by the 8th edition of the TNM classification system. Twenty-seven patients received ACRT comprising sequential administration of chemotherapy, radiotherapy (wide field), chemotherapy, radiotherapy (shrinking field), and chemotherapy. The 5-year overall survival and progression-free survival rates were 83.7% and 88.9%, respectively. Treatment compliance was 93%, which is comparable to that of previous reports. CONCLUSION: ACRT using cisplating and 5-fluorouracil was well tolerated with acceptable efficacy. LEVEL OF EVIDENCE: IVa.

DOI： 10.1016/j.bjorl.2022.12.004

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Immune checkpoint inhibitors (ICIs) have been considered as novel therapeutic approaches for various cancers. ICIs were reportedly efficacious against rare cancers, including salivary gland carcinoma (SGC). We aimed to analyze the efficacy and safety of ICIs in patients with SGC. METHODS: We retrospectively analyzed the oncologic outcomes and immune-related adverse events (irAEs) in patients with SGC treated with at least one cycle of nivolumab or pembrolizumab. RESULTS: Among 12 patients, there were two with a complete response (CR), two with a partial response, five with stable diseases, and three with progressive diseases. The overall response rate was 33.3%. A CR was achieved in patients with poorly differentiated carcinoma (carcinoma ex pleomorphic adenoma) and salivary duct carcinoma. The progression-free survival ranged between 1 and 18 months (median, 4 months), while the overall survival ranged between 2 and 25 months (median, 13.5 months). An irAE was observed in only one patient who developed grade 3 erythema multiforme, and this patient's condition improved with withdrawal of pembrolizumab alone. CONCLUSION: Programmed death-1 blockade was an effective therapy for patients with SGC, including aggressive histologic types.

DOI： 10.1002/lio2.863

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although neoantigens are one of the most favorable targets in cancer immunotherapy, it is less versatile and costly to apply neoantigen-derived cancer vaccines to patients due to individual variation. It is, therefore, important to find highly immunogenic antigens between tumor-specific or associated antigens that are shared among patients. Considering the cancer immunoediting theory, immunogenic tumor cells cannot survive in the early phase of tumor progression including two processes: elimination and equilibrium. We hypothesized that highly immunogenic molecules are allowed to be expressed in tumor cells after an immune suppressive tumor microenvironment was established, if these molecules contribute to tumor survival. In the current study, we focused on TWIST1 as a candidate for highly immunogenic antigens because it is upregulated in tumor cells under hypoxia and promotes tumor metastasis, which is observed in the late phase of tumor progression. We demonstrated that TWIST1 had an immunogenic peptide sequence TWIST1140-162 , which effectively activated TWIST1-specific CD4+ T-cells. In a short-term culture system, we detected more TWIST1-specific responses in breast cancer patients compared with in healthy donors. Vaccination with the TWIST1 peptide also showed efficient expansion of TWIST1-reactive HTLs in humanized mice. These findings indicate that TWIST1 is a highly immunogenic shared antigen and a favorable target for cancer immunotherapy.

DOI： 10.1111/cas.15429

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Novel insights into Epstein-Barr virus (EBV) pathogenicity were presented at the "19th International Symposium on Epstein-Barr Virus and Associated Diseases" in Asahikawa, Japan. In addition, basic and translational findings on EBV-associated tumors, including natural killer (NK)/T-cell lymphoma, gastric cancer, and nasopharyngeal cancer, were presented by an international group of scientists and clinicians.

DOI： 10.3390/cancers14122924

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記述言語：英語   出版者・発行元：耳鼻咽喉科臨床学会  

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記述言語：日本語   出版者・発行元：(一社)日本耳鼻咽喉科頭頸部外科学会  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: A combination therapy with immune checkpoint inhibitors (ICIs) and platinum-based chemotherapy has become the first-line treatment for recurrent or metastatic head and neck squamous carcinoma (HNSCC). Although steroids are often used as anti-emetic medications during chemotherapy, their adverse effects on immune-combined chemotherapy are unclear in HNSCC. METHODS: The effects of dexamethasone on tumor growth and immune cell population were evaluated in a mouse HNSCC model treated with PD-1 blockade combined with cisplatin. The effect of various doses of dexamethasone on cell proliferation, survival, surface markers, IFN-γ production, and antitumor effects in antigen-specific T cells was examined in vitro. The recovery of T cell dysfunction by IL-2 was assessed in vitro and in vivo. RESULTS: In a mouse HNSCC model, dexamethasone showed limited antitumor effects on immunochemotherapy. Dexamethasone decreased the number of T cells and inhibited T cell differentiation into effector and central memory T cells. In the in vitro assessment, dexamethasone induced cell death, limited proliferation, and reduced the reactivity against HNSCC cell lines of antigen-specific T cells in a dose-dependent manner. The expression of inhibitory receptors on T cells was not affected by steroids. This inhibition was recovered by IL-2 and IL-2/anti-IL-2 complexes (IL-2 Cx) in vitro and in vivo, respectively. CONCLUSION: Our preclinical data indicate that dexamethasone diminishes the antitumor effects of immunochemotherapy in patients with HNSCC. IL-2 Cx recovered the inhibition of antitumor immunity by steroids and might be a potent immune adjuvant for patients who require steroids during PD-1 blockade and chemotherapy.

DOI： 10.1016/j.tranon.2022.101358

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記述言語：日本語   出版者・発行元：日本耳鼻咽喉科免疫アレルギー感染症学会  

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記述言語：日本語   出版者・発行元：日本耳鼻咽喉科免疫アレルギー感染症学会  

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記述言語：日本語   出版者・発行元：日本耳鼻咽喉科免疫アレルギー感染症学会  

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記述言語：日本語   出版者・発行元：日本耳鼻咽喉科免疫アレルギー感染症学会  

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The success of the immune checkpoint blockade has provided a proof of concept that immune cells are capable of attacking tumors in the clinic. However, clinical benefit is only observed in less than 20% of the patients due to the non-specific activation of immune cells by the immune checkpoint blockade. Developing tumor-specific immune responses is a challenging task that can be achieved by targeting tumor antigens to generate tumor-specific T-cell responses. The recent advancements in peptide-based immunotherapy have encouraged clinicians and patients who are struggling with cancer that is otherwise non-treatable with current therapeutics. By selecting appropriate epitopes from tumor antigens with suitable adjuvants, peptides can elicit robust antitumor responses in both mice and humans. Although recent experimental data and clinical trials suggest the potency of tumor reduction by peptide-based vaccines, earlier clinical trials based on the inadequate hypothesis have misled that peptide vaccines are not efficient in eliminating tumor cells. In this review, we highlighted the recent evidence that supports the rationale of peptide-based antitumor vaccines. We also discussed the strategies to select the optimal epitope for vaccines and the mechanism of how adjuvants increase the efficacy of this promising approach to treat cancer.

DOI： 10.3390/vaccines10010070

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/coa.13876

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

A coin cell lithium battery is a common foreign body that can become lodged in the pediatric pharyngoesophageal junction. Because the voltage of such batteries is relatively high, their rapid removal is necessary to avoid mucosal necrosis. Despite being the initial choice for removal, flexible endoscopy cannot remove such foreign bodies from the esophagus. Various removal methods, including rigid esophagoscopy, should be considered for removing lithium coin cell batteries. The transcervical approach is feasible for removing esophageal foreign bodies, but it carries the risk of complications such as esophageal stenosis. Here we report a case of lithium coin battery ingestion that was successfully removed using a rigid esophagoscope. A 2-year-old girl was referred to a local doctor with cough and general fatigue. Chest X-ray and flexible endoscopy revealed a coin cell lithium battery stuck in the pharyngoesophageal junction, but it could not be removed. The foreign body was removed using Nishihata forceps through a rigid esophagoscope under general anesthesia.

DOI： 10.22037/aaem.v10i1.1430

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：耳鼻咽喉科臨床学会  

DOI： 10.5631/jibirin.115.503

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その他リンク： https://ndlsearch.ndl.go.jp/books/R000000004-I032223454

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：耳鼻咽喉科臨床学会  

DOI： 10.5631/jibirin.115.485

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その他リンク： https://ndlsearch.ndl.go.jp/books/R000000004-I032223433

記述言語：日本語   出版者・発行元：東京 : 眼科臨床紀要会  

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その他リンク： https://ndlsearch.ndl.go.jp/books/R000000004-I031935216

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Fibroblast growth factor receptor 1 (FGFR1) is overexpressed in multiple types of solid tumors, including head and neck squamous cell carcinoma (HNSCC). Being associated with poor prognosis, FGFR1 is a potential therapeutic target for aggressive tumors. T cell-based cancer immunotherapy has played a central role in novel cancer treatments. However, the potential of antitumor immunotherapy targeting FGFR1 has not been investigated. Here, we showed that FGFR-tyrosine kinase inhibitors (TKIs) augmented antitumor effects of immune checkpoint inhibitors in an HNSCC mouse model and upregulated tumoral MHC class I and MHC class II expression in vivo and in vitro. This upregulation was associated with the mitogen-activated protein kinase signaling pathway, which is a crucial pathway for cancer development through FGFR signaling. Moreover, we identified an FGFR1-derived peptide epitope (FGFR1305-319) that could elicit antigen-reactive and multiple HLA-restricted CD4+ T cell responses. These T cells showed direct cytotoxicity against tumor cells that expressed FGFR1. Notably, FGFR-TKIs augmented antitumor effects of FGFR1-reactive T cells against human HNSCC cells. These results indicate that the combination of FGFR-TKIs with immunotherapy, such as an FGFR1-targeting peptide vaccine or immune checkpoint inhibitor, could be a novel and robust immunologic approach for treating patients with FGFR1-expressing cancer cells.

DOI： 10.1080/2162402X.2021.2021619

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：一般社団法人 日本耳鼻咽喉科頭頸部外科学会  

本邦における科学技術の競争力低下が叫ばれて久しい. 医学においてもその傾向は顕著であり, 欧米では医学生が基礎研究に携わるプログラムが必須となっている一方で, 本邦においては医学生が基礎研究に触れる機会は少ない. また, 初期研修医制度によって若手医師がアカデミアから離れやすい状況が, 基礎研究を行う若手医師の減少につながっている. 現在の医学を支えているのは先人の基礎および臨床研究の蓄積であり, 研究成果を学会や論文で発表することは現代の医師が未来の患者になすべき責務と言える.

海外留学は基礎研究への専念や実験手技の習熟に有用である. さらに, 留学は主体的なプレゼンテーション能力や日本に対する俯瞰的な視点を養う場でもある. 留学先で多種多様な研究者と知己を得ることで, 自分の研究ジャンルをこえたコラボレーションや後輩たちの留学先を確保するチャンスにつながる. 臨床医が基礎研究に携わることで新たな視点から疾患を解釈して Clinical Questions および臨床と研究のシナジーを生み出すことが可能であり, これらで得られた新知見を論文化して世界に問うことが新時代の医療革命に必須である. 本稿では基礎研究の重要性および海外留学の実際, そして英語論文を執筆, 投稿する際の Tips について概説する.

DOI： 10.3950/jibiinkotokeibu.124.12_1565

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その他リンク： https://ndlsearch.ndl.go.jp/books/R000000004-I031892771

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Identification of immunogenic tumor antigens, their corresponding T cell epitopes and the selection of effective adjuvants are prerequisites for developing effective cancer immunotherapies such as therapeutic vaccines. Murine double minute 2 (MDM2) is an E3 ubiquitin-protein ligase that negatively regulates tumor suppressor p53. Because MDM2 overexpression serves as a poor prognosis factor in various types of tumors, it would be beneficial to develop MDM2-targeted cancer vaccines. In this report, we identified an MDM2-derived peptide epitope (MDM232-46) that elicited antigen-specific and tumor-reactive CD4+ T cell responses. These CD4+ T cells directly killed tumor cells via granzyme B. MDM2 is expressed in head and neck cancer patients with poor prognosis, and the T cells that recognize this MDM2 peptide were present in these patients. Notably, Nutlin-3 (MDM2-p53 blocker), inhibited tumor cell proliferation, was shown to augment antitumor T cell responses by increasing MDM2 expression, HLA-class I and HLA-DR through class II transactivator (CIITA). These results suggest that the use of this MDM2 peptide as a therapeutic vaccine combined with MDM2 inhibitors could represent an effective immunologic strategy to treat cancer.

DOI： 10.1007/s00262-021-02940-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Activation of STING signaling plays an important role in anti-tumor immunity, and we previously reported the anti-tumor effects of STING through accumulation of M1-like macrophages in tumor tissue treated with a STING agonist. However, myeloid cells express SIRPα, an inhibitory receptor for phagocytosis, and its receptor, CD47, is overexpressed in various cancer types. Based on our findings that breast cancer patients with highly expressed CD47 have poor survival, we evaluated the therapeutic efficacy and underlying mechanisms of combination therapy with the STING ligand cGAMP and an antagonistic anti-CD47 mAb using E0771 mouse breast cancer cells. Anti-CD47 mAb monotherapy did not suppress tumor growth in our setting, whereas cGAMP and anti-CD47 mAb combination therapy inhibited tumor growth. The combination therapy enhanced phagocytosis of tumor cells and induced systemic anti-tumor immune responses, which rely on STING and type I IFN signaling. Taken together, our findings indicate that coadministration of cGAMP and an antagonistic anti-CD47 mAb may be promising for effective cancer immunotherapy.

DOI： 10.1084/jem.20200792

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記述言語：日本語   出版者・発行元：(一社)日本鼻科学会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/jha2.233

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Stimulator of interferon genes (STING) contributes to anti-tumor immunity by activating antigen-presenting cells and inducing mobilization of tumor-specific T cells. A role for tumor-migrating neutrophils in the anti-tumor effect of STING-activating therapy has not been defined. We used mouse tumor transplantation models for assessing neutrophil migration into the tumor triggered by intratumoral treatment with STING agonist, 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). Intratumoral STING activation with cGAMP enhanced neutrophil migration into the tumor in an NF-κB/CXCL1/2-dependent manner. Blocking the neutrophil migration by anti-CXCR2 monoclonal antibody impaired T cell activation in tumor-draining lymph nodes (dLNs) and efficacy of intratumoral cGAMP treatment. Moreover, the intratumoral cGAMP treatment did not show any anti-tumor effect in type I interferon (IFN) signal-impaired mice in spite of enhanced neutrophil accumulation in the tumor. These results suggest that both neutrophil migration and type I interferon (IFN) induction by intratumoral cGAMP treatment were critical for T-cell activation of dLNs and the anti-tumor effect. In addition, we also performed in vitro analysis showing enhanced cytotoxicity of neutrophils by IFN-β1. Extrinsic STING activation triggers anti-tumor immune responses by recruiting and activating neutrophils in the tumor via two signaling pathways, CXCL1/2 and type I IFNs.

DOI： 10.1007/s00262-021-02864-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recent studies have revealed that tumor cells decrease their immunogenicity by epigenetically repressing the expression of highly immunogenic antigens to survive in immunocompetent hosts. We hypothesized that these epigenetically hidden "stealth" antigens should be favorable targets for cancer immunotherapy due to their high immunogenicity. To identify these stealth antigens, we treated human lung cell line A549 with DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5Aza) and its prodrug guadecitabine for 3 d in vitro and screened it using cDNA microarray analysis. We found that the gene encoding sperm equatorial segment protein 1 (SPESP1) was re-expressed in cell lines including solid tumors and leukemias treated with 5Aza, although SPESP1 was not detected in untreated tumor cell lines. Using normal human tissue cDNA panels, we demonstrated that SPESP1 was not detected in normal human tissue except for testis and placenta. Moreover, we found using immunohistochemistry SPESP1 re-expression in xenografts in BALB/c-nu/nu mice that received 5Aza treatment. To assess the antigenicity of SPESP1, we stimulated human CD4+ T-cells with a SPESP1-derived peptide designed using a computer algorithm. After repetitive stimulation, SPESP1-specific helper T-cells were obtained; these cells produced interferon-γ against HLA-matched tumor cell lines treated with 5Aza. We also detected SPESP1 expression in freshly collected tumor cells derived from patients with acute myeloid leukemia or lung cancer. In conclusion, SPESP1 can be classified as a stealth antigen, a molecule encoded by a gene that is epigenetically silenced in tumor cells but serves as a highly immunogenic antigen suitable for cancer immunotherapy.

DOI： 10.1111/cas.14973

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Extranodal NK/T-Cell Lymphoma, nasal type (ENKTL-NT) has some salient aspects. The lymphoma is commonly seen in Eastern Asia, has progressive necrotic lesions in the nasal cavity, makes midfacial destructive lesions, and shows poor prognosis. The lymphoma cell is originated from either NK- or γδ T-cells, which express CD56. Since the authors first demonstrated the existence of Epstein-Barr virus (EBV) DNA and EBV oncogenic proteins in lymphoma cells, ENKTL-NT has been recognized as an EBV-associated malignancy. Because the angiocentric and polymorphous lymphoma cells are mixed with inflammatory cells on a necrotic background, the diagnosis of ENKTL-NT requires CD56 immunostaining and EBER in situ hybridization. In addition, serum the EBV DNA level is useful for the diagnosis and monitoring of ENKTL-NT. Although ENKTL-NT is refractory lymphoma, the prognosis is improved by the development of therapies such as concomitant chemoradiotherapy. The basic research reveals that a wide variety of intracellular/cell surface molecules, cytokines, chemokines, and micro RNAs are involved in lymphomagenesis, and some of them are related to EBV. Understanding lymphoma behavior introduces new therapeutic strategies, such as the usage of immune checkpoint inhibitors, peptide vaccines, and molecular targeting therapy. This review addresses recent advances in basic and clinical aspects of ENKTL-NT, especially its relation to EBV features.

DOI： 10.3390/microorganisms9071381

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記述言語：日本語   出版者・発行元：日本喉頭科学会  

DOI： 10.5426/larynx.33.31

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その他リンク： https://search.jamas.or.jp/link/ui/2022112462

記述言語：日本語   出版者・発行元：日本耳鼻咽喉科免疫アレルギー感染症学会  

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記述言語：日本語   出版者・発行元：(一社)日本頭頸部癌学会  

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記述言語：日本語   出版者・発行元：日本耳鼻咽喉科免疫アレルギー感染症学会  

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記述言語：日本語   出版者・発行元：日本耳鼻咽喉科免疫アレルギー感染症学会  

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記述言語：日本語   出版者・発行元：(一社)日本耳鼻咽喉科頭頸部外科学会  

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記述言語：日本語   出版者・発行元：(一社)日本耳鼻咽喉科頭頸部外科学会  

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: We analyzed the effects of early nutritional intervention by a nutritional support team (NST) in patients with head and neck squamous cell carcinoma (HNSCC) undergoing chemoradiotherapy or radiotherapy. METHODS: This study investigated whether early nutritional interventions by a multidisciplinary NST improve body weight loss, mucositis, serum albumin level, and hospital length of stay. RESULTS: Sixty-one patients with HNSCC were treated during the study, and 32 patients received NST intervention since admission. The median weight loss rates were 3.3% and 7.3% and grade 3 mucositis was observed in 25.0% and 70.0% of patients in the intervention and nonintervention groups, respectively. In the intervention group, serum albumin level through treatment increased and the hospital length of stay from the end of treatment was shortened. CONCLUSION: Early nutritional intervention by a multidisciplinary NST improved body weight loss rate, mucositis, albumin level, and hospital length of stay, which might lead to better clinical outcomes.

DOI： 10.1002/hed.26502

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：耳鼻咽喉科臨床学会  

DOI： 10.5631/jibirin.114.801

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その他リンク： https://ndlsearch.ndl.go.jp/books/R000000004-I031757885

担当区分：筆頭著者   記述言語：日本語   出版者・発行元：日本口腔・咽頭科学会  

慢性上咽頭炎はいまだその定義が確立していない疾患であるが，後鼻漏や咽頭痛などの局所症状に加えて，IgA腎症を含む自己免疫疾患（TIAS）や慢性疲労症候群などの全身疾患にも関連することが知られている．その病態に関してはいまだに仮説の域を出ない側面が多く，上咽頭を専門領域の一つとして扱う耳鼻咽喉科医がその病態を解明していくことが期待される．本稿では，慢性上咽頭炎の病態を局所の炎症，自律神経のインバランス，脳脊髄液の環流障害といった側面から考察し，慢性上咽頭炎および本疾患が関与しえる疾患や症状の病態について概説する．

DOI： 10.14821/stomatopharyngology.34.157

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その他リンク： https://ndlsearch.ndl.go.jp/books/R000000004-I032533165

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：耳鼻咽喉科臨床学会  

DOI： 10.5631/jibirin.114.231

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その他リンク： https://ndlsearch.ndl.go.jp/books/R000000004-I031317815

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：耳鼻咽喉科臨床学会  

DOI： 10.5631/jibirin.114.373

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その他リンク： https://ndlsearch.ndl.go.jp/books/R000000004-I031498545

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：耳鼻咽喉科臨床学会  

DOI： 10.5631/jibirin.114.553

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その他リンク： https://ndlsearch.ndl.go.jp/books/R000000004-I031604893

担当区分：筆頭著者   記述言語：日本語   出版者・発行元：日本耳鼻咽喉科免疫アレルギー感染症学会  

20世紀後半よりウイルスが発癌に寄与することが次々と明らかにされてきた。頭頸部は多くの病原体が侵入する経路であり，耳鼻咽喉科・頭頸部外科医が加療する疾患においてもヒトパピローマウイルスやEpstein Barrウイルス（EBウイルス）が中咽頭癌や上咽頭癌の発生や進行に関わっている。鼻性NK/T細胞リンパ腫は頭頸部を主座とする致死的な疾患であり，病理学的診断が非常に困難なことで知られる。1990年にEBウイルスが本リンパ腫細胞に発現することが明らかとなり，EBウイルス関連ゲノム（EB virus-encoded small RNAs：EBER）のIn situ hybridizationによる検出が本疾患の診断に役立ってきた。さらに血中のEBウイルスDNA量が病勢に応じたマーカーとして臨床応用され，ウイルス発癌の特性が実臨床にも生かされてきたと言える。近年，EBウイルス由来タンパクであるLMP1が本疾患の病態に関わるメカニズムの解明に加え，EBウイルス由来タンパクを治療標的としたペプチドワクチンの開発が進んできた。本稿では，EBウイルスを中心とした本疾患の病態解明および本疾患を取り巻く免疫微小環境，今後の治療戦略について概説する。

DOI： 10.24805/jiaio.1.3_147

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記述言語：日本語   出版者・発行元：日本鼻科学会  

日本鼻科学会では，鼻科学会会員を対象とした『鼻科基礎ハンズオンセミナー』を2014年より開催している。鼻科基礎ハンズオンセミナーは，研究技術の向上や研究に対するモチベーションの向上，そして各施設間の研究を通じた横断的連携を図る目的で企画された。本セミナーは，基礎研究を行っている全国の各施設の医師より構成されている。今回で7回目となる本セミナーを第59回日本鼻科学会総会・学術講演会（東京）において企画した。今年度は，①末梢血からの単核球細胞の分離，②鼻茸組織からの単核球細胞の分離，③口蓋扁桃組織からの単核球細胞の分離方法を解説した。例年では会場で直接手技を実演，指導する形式で行っていたが，新型コロナ感染症の蔓延により，事前に収録した動画を放映し，参加者からの質疑応答を行うオンライン方式で行った。参加者に対するセミナー後のアンケート調査において，「本セミナーに満足した」，「今後の継続を望む」という意見を得ている。本セミナーは本邦から発信する基礎鼻科学の新知見に直結する有意義なセミナーと考えられた。

DOI： 10.7248/jjrhi.60.566

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記述言語：日本語   出版者・発行元：特定非営利活動法人 日本頭頸部外科学会  

新型コロナウイルス陽性患者（COVID-19）に対する気管切開術を2症例経験した。症例1は80代男性。長期間の気管挿管管理が必要となり，N95マスクを使用したFull PPEにて気管切開を施行した。症例2は60代男性。1例目の気管切開では視野の確保が困難であった点を踏まえて，電動ファン付き呼吸⽤防護具（PAPR：powered air-purifying respirator）下で外科的気管切開を行った。PAPRを用いることで，Full PPEで外科的気管切開を行う上での視野確保における問題点を解決できており，安全な感染制御下での外科的気管切開に有用と考えられた。

DOI： 10.5106/jjshns.21-006

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記述言語：日本語   出版者・発行元：日本小児耳鼻咽喉科学会  

バーキットリンパ腫は高悪性度B細胞リンパ腫である。小児では発熱や体重減少などの全身症状を呈することは少なく，原発部位による多彩な症状が出現するが，これらの症状を契機に病院受診されることが多い。鼻副鼻腔を原発とする悪性リンパ腫は非常に稀であるが，今回，急速な視力障害を呈した小児副鼻腔バーキットリンパ腫の2例を経験したので考察を加えてここに報告する。

両症例ともに急速な視力障害の症状を認めた。画像検査にていずれも鼻副鼻腔に腫瘤性病変を認め，生検にてバーキットリンパ腫の診断となった。化学療法を施行し，両症例とも完全寛解の状態であるが，1例では視力の改善が得られなかった。バーキットリンパ腫は急速に進行し，周囲臓器へ浸潤傾向を示すため早期の診断・治療が重要である。

DOI： 10.11374/shonijibi.42.342

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その他リンク： https://ndlsearch.ndl.go.jp/books/R000000004-I032540742

記述言語：日本語   出版者・発行元：日本鼻科学会  

Thyroid-like low grade nasopharyngeal papillary adenocarcinoma（TL-LGNPPA）は甲状腺乳頭癌様の病理所見を示し，免疫染色でTTF-1陽性，TG陰性となる特徴を持つ上咽頭や鼻中隔後端に発生する珍しい悪性腫瘍である。今回われわれは鼻中隔後端に発生したNasopharyngeal papillary adenocarcinoma（NPPA）の一例を経験したので文献的考察を加え報告する。

症例は50歳女性で，咽頭違和感を主訴に前医を受診した際，鼻中隔後端に腫瘤を指摘され当科紹介となった。経鼻内視鏡検査で鼻中隔後端に有茎性の腫瘤を認め，造影CTでは鼻中隔後端に6 mm大の有茎性腫瘤，造影MRIでは病変部はT1，T2ともに正常粘膜と同程度の信号である腫瘍が確認できた。腫瘍生検を施行したところ，TL-LGNPPAの所見でTTF-1陽性，TG陰性であった。全身麻酔下に内視鏡を用いて鼻中隔後端の腫瘤を完全摘出した。手術標本の病理所見では断端陰性であり，追加治療は行わなかった。また明らかな術後合併症は認めず，術後1年6ヶ月経過したが明らかな再発や転移の所見は認めていない。

DOI： 10.7248/jjrhi.60.495

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その他リンク： https://search.jamas.or.jp/link/ui/2022105062

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Placenta-specific 1 (PLAC1) is expressed primarily in placental trophoblasts but not in normal tissues and is a targetable candidate for cancer immunotherapy because it is a cancer testis antigen known to be up-regulated in various tumors. Although peptide epitopes capable of stimulating CD8 T cells have been previously described, there have been no reports of PLAC1 CD4 helper T lymphocyte (HTL) epitopes and the expression of this antigen in head and neck squamous cell carcinoma (HNSCC). Here, we show that PLAC1 is highly expressed in 74.5% of oropharyngeal and 51.9% of oral cavity tumors from HNSCC patients and in several HNSCC established cell lines. We also identified an HTL peptide epitope (PLAC131-50) capable of eliciting effective antigen-specific and tumor-reactive T cell responses. Notably, this peptide behaves as a promiscuous epitope capable of stimulating T cells in the context of more than one human leukocyte antigen (HLA)-DR allele and induces PLAC1-specific CD4 T cells that kill PLAC1-positive HNSCC cell lines in an HLA-DR-restricted manner. Furthermore, T-cells reactive to PLAC131-50 peptide were detected in the peripheral blood of HNSCC patients. These findings suggest that PLAC1 represents a potential target antigen for HTL based immunotherapy in HNSCC.

DOI： 10.1080/2162402X.2020.1856545

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記述言語：日本語   出版者・発行元：日本喉頭科学会  

DOI： 10.5426/larynx.32.189

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その他リンク： https://search.jamas.or.jp/link/ui/2021130319

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

PD-1 blockade is a feasible approach in treating mucosal malignant melanomas of the middle ear.

DOI： 10.1002/ccr3.3424

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記述言語：日本語   出版者・発行元：(一社)日本鼻科学会  

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jpeds.2020.06.010

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記述言語：日本語   出版者・発行元：日本がん免疫学会  

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記述言語：日本語   出版者・発行元：日本がん免疫学会  

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記述言語：日本語   出版者・発行元：特定非営利活動法人 日本気管食道科学会  

副甲状腺嚢胞は頸部腫脹を呈する良性疾患で，機能性が10％，非機能性が90％を占める。機能性である場合は，嚢胞液の経皮的吸引や外科的切除が推奨される。Video-assisted neck surgery（以下VANS法）は，頸部切開手術と比較し安全面では劣らないにもかかわらず，術後の創部は衣服で隠れるため，審美性に優れているという利点がある。また，血管や神経，副甲状腺が拡大視野で確認可能であるという利点もある。近年VANS法による甲状腺腫瘍の手術報告は多いが，副甲状腺腫瘍の外科的治療では，頸部切開による単腺摘出（focused approach）が行われることが多く，VANS法による副甲状腺腫瘍摘出術の報告例は少ない。今回われわれは，機能性，非機能性副甲状腺嚢胞において，VANS法で摘出した2例を経験したのでここに報告する。

DOI： 10.2468/jbes.71.325

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その他リンク： https://ndlsearch.ndl.go.jp/books/R000000004-I030602931

記述言語：日本語   出版者・発行元：(一社)日本頭頸部癌学会  

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記述言語：日本語   出版者・発行元：日本喉頭科学会  

DOI： 10.5426/larynx.32.73

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その他リンク： https://search.jamas.or.jp/link/ui/2021000989

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Colorectal cancer (CRC) patients with metastatic lesions have low 5-year survival rates. During metastasis, cancer cells often obtain unique characteristics such as epithelial-mesenchymal transition (EMT). Vimentin a biomarker contributes to EMT by changing cell shape and motility. Since abnormal phosphorylation is a hallmark of malignancy, targeting phosphorylated vimentin is a feasible approach for the treatment of metastatic tumors while sparing non-tumor cells. Recent evidence has revealed that both CD8 cytotoxic T lymphocytes (CTLs) and also CD4 helper T lymphocytes (HTLs) can distinguish post-translationally modified antigens from normal antigens. Here, we showed that the expression of phosphorylated vimentin was upregulated in metastatic sites of CRC. We also showed that a chemotherapeutic reagent augmented the expression of phosphorylated vimentin. The novel phosphorylated helper peptide epitopes from vimentin could elicit a sufficient T cell response. Notably, precursor lymphocytes that specifically reacted to these phosphorylated vimentin-derived peptides were detected in CRC patients. These results suggest that immunotherapy targeting phosphorylated vimentin could be promising for metastatic CRC patients.

DOI： 10.1007/s00262-020-02524-9

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：日本耳鼻咽喉科感染症・エアロゾル学会  

かぜ症候群は上気道に急性炎症をきたす疾患であり，鼻漏や鼻閉などの鼻症状や咽頭痛を呈するため耳鼻咽喉科を受診する機会が多い．かぜ症候群は予後が良好な疾患として広く知られており，医療従事者を含めて軽視されがちな疾患である．しかし，症候学的見地から見ると鼻症状や咽頭痛，頭痛，発熱，全身倦怠感といった症状には重症化する疾患が数多く潜んでいる．また，高齢者や基礎疾患を有する患者では，ウイルス感染によるかぜ症候群から重症感染症に移行する可能性がある．超高齢化社会を迎えた本邦において，外来では健康に見える高齢者でも実際には予備力が低下しており，軽微な感染症によってパフォーマンスステイタスが不可逆的に低下する症例をしばしば経験する．本稿では，高齢者や基礎疾患を有しているハイリスク患者の“かぜ”症状に焦点をあて，ハイリスクの定義およびかぜ症候群と鑑別を要する疾患について概説する．

DOI： 10.24805/jjsiao.8.2_129

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although cisplatin (CDDP) has been used as a major chemotherapeutic drug for head and neck squamous cell carcinoma (HNSCC), its impact on T-cell functions is controversial. Therefore, we investigated the immunologic effects of CDDP and antitumor effects by combination therapy of CDDP with a ligand for stimulator of interferon genes, cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). Direct impacts of CDDP on T-cell functions were addressed by comparing T-cell functions between human subjects treated and untreated with CDDP. The immune responses and the efficacy of combination therapy using CDDP and cGAMP were assessed using BALB/c mice inoculated with mouse squamous cell carcinoma (SCC) cell lines. CDDP inhibited T-cell proliferation in a dose-dependent manner. T-cell functions of CDDP-treated HNSCC patients were comparable to those of healthy donors and CDDP-untreated HNSCC patients. In the mice bearing SCC cell lines, combination therapy using CDDP and cGAMP enhanced the gene expressions of CXCL9 and CXCL10 in the tumor tissues and inhibited tumor growth. The antitumor effect was cancelled by anti-CXCR3 monoclonal antibody. These findings suggest that the combination therapy using CDDP and an immunomodulating drug like cGAMP would be a rational cancer immunotherapy for patients with HNSCC.

DOI： 10.1016/j.bbrc.2019.11.107

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記述言語：日本語   出版者・発行元：日本耳鼻咽喉科感染症・エアロゾル学会  

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The effect of PD-1 blockade as a first-line therapy in nonmetastatic head and neck squamous cell carcinoma (HNSCC) remains unknown. We report a case of an exceptional response to PD-1 blockade as a first-line therapy in a patient with HNSCC and lung cancer. A 59-year-old man presented with cheek swelling and chest pain. He was diagnosed with maxillary sinus carcinoma (squamous cell carcinoma) and lung cancer (non-small-cell lung cancer, not otherwise specified). The maxillary sinus carcinoma was completely resolved after 8 cycles of pembrolizumab. Immune checkpoint blockade warrants further evaluation in previously untreated patients with HNSCC.

DOI： 10.1159/000509485

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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記述言語：日本語   出版者・発行元：日本口腔・咽頭科学会  

症例は69歳女性で主訴は硬口蓋腫瘤．右硬口蓋に正常粘膜に覆われた弾性硬の腫瘤が突出していた．生検にて筋上皮腫の診断となり摘出術を行った．病理組織所見では上皮様の組織が主体を占めていたが，紡錘細胞様，形質細胞様，明細胞様の組織も混在していた．免疫染色では筋上皮系のマーカーであるactin，αSMA，S-100proteinの他にGFAPが陽性であった．悪性化の指標であるMIB-1 indexは5％で良性を示唆していた．以上より筋上皮腫（混合型）の診断となった．術後10ヵ月経過した現在再発なく経過しているが，再発や悪性化の報告もあり今後も注意深い経過観察が必要と考えられた．

DOI： 10.14821/stomatopharyngology.33.45

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その他リンク： https://ndlsearch.ndl.go.jp/books/R000000004-I032538511

記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：耳鼻咽喉科臨床学会  

DOI： 10.5631/JIBIRIN.113.787

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その他リンク： https://ndlsearch.ndl.go.jp/books/R000000004-I030799723

記述言語：日本語   出版者・発行元：(一社)日本耳科学会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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記述言語：英語   出版者・発行元：(一社)日本癌学会  

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

IgA nephropathy (IgAN) is a tonsil-related disease. We previously showed that oligodeoxynucleotides with CpG (CpG-ODN) and B-cell activation factor (BAFF) are involved in hyperproduction of IgA from tonsillar mononuclear cells of patients with IgAN (IgAN-TMCs). In this study, we focused on a proliferation-inducing ligand (APRIL), homologous to BAFF. IgAN-TMCs produced more APRIL than non IgAN-TMCs in the presence of both CpG-ODN and control-ODN. TLR9 expression was higher in B-cells of IgAN-TMCs, and treatment with CpG-ODN enhanced transmembrane activator and CAML interactor (TACI) expression. IgA production from IgAN-TMCs was inhibited by APRIL neutralization antibody or TACI blocking antibody, and enhanced by co-treatment of APRIL and CpG-ODN. Serum APRIL levels were higher in patients with IgAN, and decreased after tonsillectomy. These findings suggest that APRIL is involved in the hyperproduction of IgA from IgAN-TMCs, and that CpG-ODN enhanced APRIL-induced IgA production by increasing TACI expression on B-cells of IgAN-TMCs.

DOI： 10.1016/j.cellimm.2019.103925

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) originates from squamous epithelium of the upper aerodigestive tract and is the most common malignancy in the head and neck region. Among HNSCCs, oropharynx squamous cell carcinoma (OSCC) has a unique profile and is associated with human papillomavirus infection. Recently, anti-programmed cell death-1 monoclonal antibody has yielded good clinical responses in recurrent and/or metastatic HNSCC patients. Therefore, programmed death-ligand 1 (PD-L1) may be a favorable target molecule for cancer immunotherapy. Although PD-L1-expressing malignant cells could be targeted by PD-L1-specific CD8+ cytotoxic T lymphocytes, it remains unclear whether CD4+ helper T lymphocytes (HTLs) recognize and kill tumor cells in a PD-L1-specific manner. METHODS: The expression levels of PD-L1 and HLA-DR were evaluated using immunohistochemical analyses. MHC class II-binding peptides for PD-L1 were designed based on computer algorithm analyses and added into in vitro culture of HTLs with antigen-presenting cells to evaluate their stimulatory activity. RESULTS: We found that seven of 24 cases of OSCC showed positive for both PD-L1 and HLA-DR and that PD-L1241-265 peptide efficiently activates HTLs, which showed not only cytokine production but also cytotoxicity against tumor cells in a PD-L1-dependent manner. Also, an adoptive transfer of the PD-L1-specific HTLs significantly inhibited growth of PD-L1-expressing human tumor cell lines in an immunodeficient mouse model. Importantly, T cell responses specific for the PD-L1241-265 peptide were detected in the HNSCC patients. CONCLUSIONS: The cancer immunotherapy targeting PD-L1 as a helper T-cell antigen would be a rational strategy for HNSCC patients.

DOI： 10.1186/s12967-019-1957-5

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：耳鼻咽喉科展望会  

DOI： 10.11453/orltokyo.62.supplement1_s34

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：日本喉頭科学会  

DOI： 10.5426/larynx.31.34

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その他リンク： https://search.jamas.or.jp/link/ui/2019300654

記述言語：日本語   出版者・発行元：耳鼻咽喉科臨床学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nasal natural killer/T-cell lymphoma (NNKTL) is closely associated with Epstein-Barr virus (EBV) and is characterized by poor prognosis, resulting from rapid progression of lesions in the affected organs. Recent data have shown that NNKTL is associated with the aberrant expression of cyclin-dependent kinase 1 (CDK1) and its downstream target survivin, but little is known about the functional roles of CDK1 and survivin in NNKTL. In the current study, we show that knockdown of the EBV-encoded oncoprotein latent membrane protein 1 (LMP1) induces downregulation of CDK1 and survivin in NNKTL cells. Immunohistochemistry detected CDK1 and survivin expression in LMP1-positive cells of NNKTL biopsy specimens. Inhibition of CDK1 and survivin in NNKTL cells with several inhibitors led to a dose-dependent decrease in cell proliferation. In addition, the Sp1 inhibitor mithramycin, which can downregulate both CDK1 and survivin, significantly suppressed the growth of established NNKTL in a murine xenograft model. Our results suggest that LMP1 upregulation of CDK1 and survivin may be essential for NNKTL progression. Furthermore, targeting CDK1 and survivin with Sp1 inhibitors such as mithramycin may be an effective approach to treat NNKTL, which is considered to be a treatment-refractory lymphoma.

DOI： 10.1038/s41374-018-0182-9

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記述言語：日本語   出版者・発行元：(一社)日本アレルギー学会  

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記述言語：日本語   出版者・発行元：(一社)日本アレルギー学会  

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Vaccines consisting of synthetic peptides representing cytotoxic T-lymphocyte (CTL) epitopes have long been considered as a simple and cost-effective approach to treat cancer. However, the efficacy of these vaccines in the clinic in patients with measurable disease remains questionable. We believe that the poor performance of peptide vaccines is due to their inability to generate sufficiently large CTL responses that are required to have a positive impact against established tumors. Peptide vaccines to elicit CTLs in the clinic have routinely been administered in the same manner as vaccines designed to induce antibody responses: injected subcutaneously and in many instances using Freund's adjuvant. We report here that peptide vaccines and poly-ICLC adjuvant administered via the unconventional intravenous route of immunization generate substantially higher CTL responses as compared to conventional subcutaneous injections, resulting in more successful antitumor effects in mice. Furthermore, amphiphilic antigen constructs such as palmitoylated peptides were shown to be better immunogens than long peptide constructs, which now are in vogue in the clinic. The present findings if translated into the clinical setting could help dissipate the wide-spread skepticism of whether peptide vaccines will ever work to treat cancer.

DOI： 10.1007/s00262-018-02294-5

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担当区分：筆頭著者,　最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Extranodal natural killer (NK)/T-cell lymphoma, nasal type (NNKTL) has very unique epidemiological, etiologic, histologic, and clinical characteristics. It is commonly observed in Eastern Asia, but quite rare in the United States and Europe. The progressive necrotic lesions mainly in the nasal cavity, poor prognosis caused by rapid local progression with distant metastases, and angiocentric and polymorphous lymphoreticular infiltrates are the main clinical and histologic features. Phenotypic and genotypic studies revealed that the lymphoma is originated from either NK- or γδ T-cell, both of which express CD56. In 1990, the authors first reported the presence of Epstein-Barr virus (EBV)-DNA and EBV-oncogenic proteins, and EBV has now been recognized to play an etiological role in NNKTL. in vitro studies revealed that a wide variety of cytokines, chemokines, and micro RNAs, which may be produced by EBV-oncogenic proteins in the lymphoma cells, play important roles for tumor progression in NNKTL, and could be therapeutic targets. In addition, it was revealed that the interaction between NNKTL cells and immune cells such as monocytes and macrophages in NNKTL tissues contribute to lymphoma progression. For diagnosis, monitoring the clinical course and predicting prognosis, the measurements of EBV-DNAs and EBV-micro RNAs in sera are very useful. For treatment with early stage, novel concomitant chemoradiotherapy such as DeVIC regimen with local radiotherapy and MPVIC-P regimen using intra-arterial infusion developed with concomitant radiotherapy and the prognosis became noticeably better. However, the prognosis of patients with advanced stage was still poor. Establishment of novel treatments such as the usage of immune checkpoint inhibitor or peptide vaccine with molecular targeting therapy will be necessary. This review addresses recent advances in the molecular understanding of NNKTL to establish novel treatments, in addition to the epidemiologic, clinical, pathological, and EBV features.

DOI： 10.3389/fped.2019.00141

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：日本鼻科学会  

日本鼻科学会では，2014年より学会主導による『鼻科基礎ハンズオンセミナー』を開催している。これは，耳鼻咽喉科臨床医の基礎研究に対するモチベーションや研究技術の向上，ひいては各大学間の研究を通じた横断的連携を図る目的で企画された。幸いなことに本セミナーへの期待度は非常に高く，セミナー後のアンケート調査ではこれまで継続を希望する意見が多数であった。今回で5回目となる本セミナーを第57回日本鼻科学会総会・学術講演会（旭川）において企画した。今年度は①鼻・副鼻腔サンプルからの細胞単離および，mRNA抽出，②ELISA，③Western Blot，そして④CRISPER-Cas9の4テーマをそれぞれのブースで実演する形式とし，セミナー終了後に参加者にアンケート調査を実施した。全回答者から「大変良かった」または「良かった」という高評価を得ており，96％の参加者より「今後の継続を望む」という意見を得ている。今回，多数の大学院生や大学スタッフが参加しており，本邦から発信する基礎鼻科学の新知見に直結する有意義なセミナーと考えられた。

DOI： 10.7248/jjrhi.58.152

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その他リンク： https://search.jamas.or.jp/link/ui/2023114525

記述言語：日本語   出版者・発行元：日本鼻科学会  

リンパ節外領域である副鼻腔原発の悪性リンパ腫は頭頸部原発の悪性リンパ腫の中でもまれで，他部位と比較して予後不良とされる。今回当科で経験した副鼻腔原発の悪性リンパ腫5例について検討した。症例は男性が3人，女性が2人で年齢は55歳から84歳（中央値75歳）であった。亜部位は全例で上顎洞であった。組織型はびまん性大細胞型B細胞リンパ腫が3例，濾胞性リンパ腫が1例，高悪性度B細胞リンパ腫非特異型が1例であった。病期はAnn Arbor分類でI期が2例，II期が2例，IV期が1例であった。B症状は全例で認めなかった。治療は化学療法施行後に放射線療法を施行した症例が3例，化学療法のみを施行した症例が1例，放射線療法のみを施行した症例が1例であった。初回治療では全例でCRとなったが，2例で再発した。追加治療を含めて80％の症例でCRとなった。リツキシマブを中心とした化学療法や放射線療法は副鼻腔原発のB細胞性悪性リンパ腫の治療に有用と考えられた。

DOI： 10.7248/jjrhi.58.698

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担当区分：筆頭著者   記述言語：日本語   出版者・発行元：日本鼻科学会  

DOI： 10.7248/jjrhi.58.107

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その他リンク： https://search.jamas.or.jp/link/ui/2019308332

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cytotoxic T lymphocytes (CTLs) are effective components of the immune system capable of destroying tumor cells. Generation of CTLs using peptide vaccines is a practical approach to treat cancer. We have previously described a peptide vaccination strategy that generates vast numbers of endogenous tumor-reactive CTLs after two sequential immunizations (prime-boost) using poly-ICLC adjuvant, which stimulates endosomal toll-like receptor 3 (TLR3) and cytoplasmic melanoma differentiation antigen 5 (MDA5). Dendritic cells (DCs) play an important role not only in antigen presentation but are critical in generating costimulatory cytokines that promote CTL expansion. Poly-ICLC was shown to be more effective than poly-IC in generating type-I interferon (IFN-I) in various DC subsets, through its enhanced ability to escape the endosomal compartment and stimulate MDA5. In our system, IFN-I did not directly function as a T cell costimulatory cytokine, but enhanced CTL expansion through the induction of IL15. With palmitoylated peptide vaccines, CD8α+ DCs were essential for peptide crosspresentation. For vaccine boosts, non-professional antigen-presenting cells were able to present minimal epitope peptides, but DCs were still required for CTL expansions through the production of IFN-I mediated by poly-ICLC. Overall, these results clarify the roles of DCs, TLR3, MDA5, IFN-I and IL15 in the generation of vast and effective antitumor CTL responses using peptide and poly-IC vaccines.

DOI： 10.1007/s00262-018-2164-6

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記述言語：日本語   出版者・発行元：耳鼻咽喉科臨床学会  

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Peptide vaccines can be a successful and cost-effective way of generating T-cell responses against defined tumor antigens, especially when combined with immune adjuvants such as poly-IC. However, strong immune adjuvants can induce a collateral increase in numbers of irrelevant, nonspecific T cells, which limits the effectiveness of the peptide vaccines. Here, we report that providing prolonged IL2 signaling in the form of either IL2/anti-IL2 complexes or pegylated IL2 overcomes the competitive suppressive effect of irrelevant T cells, allowing the preferential expansion of antigen-specific T cells. In addition to increasing the number of tumor-reactive T cells, sustained IL2 enhanced the ability of T cells to resist PD-1-induced negative signals, increasing the therapeutic effectiveness of the vaccines against established tumors. This vaccination strategy using peptides and sustained IL2 could be taken into the clinic for the treatment of cancer. Cancer Immunol Res; 6(5); 617-27. ©2018 AACR.

DOI： 10.1158/2326-6066.CIR-17-0549

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The human T cell receptor is capable of distinguishing between normal and post-translationally modified peptides. Because aberrant phosphorylation of cellular proteins is a hallmark of malignant transformation, the expression of the phosphorylated epitope could be an ideal antigen to combat cancer without damaging normal tissues. p53 activates transcription factors to suppress tumors by upregulating growth arrest and apoptosis-related genes. In response to DNA damage, p53 is phosphorylated at multiple sites including Ser33 and Ser37. Here, we identified phosphorylated peptide epitopes from p53 that could elicit effective T helper responses. These epitope peptides, p5322-41/Phospho-S33 and p5322-41/Phospho-S37, induced T helper responses against tumor cells expressing the phosphorylated p53 protein. Moreover, chemotherapeutic agents augmented the responses of such CD4 T cells via upregulation of phosphorylated p53. The upregulation of phosphorylated p53 expression by chemotherapy was confirmed in in vitro and xenograft models. We evaluated phosphorylated p53 expression in the clinical samples of oropharyngeal squamous cell carcinoma and revealed that 13/24 cases (54%) were positive for phosphorylated p53. Importantly, the lymphocytes specific for the phosphorylated p53 peptide epitopes were observed in the head and neck squamous cell cancer (HNSCC) patients. These results reveal that a combination of phosphorylated p53 peptides and chemotherapy could be a novel immunologic approach to treat HNSCC patients.

DOI： 10.1080/2162402X.2018.1466771

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：日本耳鼻咽喉科免疫アレルギー学会  

鼻性NK/T細胞リンパ腫は鼻腔や口蓋といった顔面正中部に生じるNKまたはγδT細胞由来のEBウイルス関連悪性リンパ腫である。病理組織学的に，腫瘍組織内にリンパ球や単球，マクロファージなどの炎症細胞浸潤が著明であるという特徴を有する。腫瘍細胞内に外来抗原であるEBウイルス由来蛋白を有し，腫瘍組織内にリンパ球浸潤が著しいにも関わらず，免疫系が腫瘍細胞を排除できないことから，本疾患は腫瘍免疫系を回避・抑制する複数のメカニズムを有していると思われる。我々は本疾患に対して，エピトープペプチドを用いて腫瘍抗原特異的CD4陽性ヘルパーT細胞を賦活化するペプチド免疫療法の基礎的研究を続けてきた。EBウイルス関連腫瘍である本疾患では，非自己であるEBウイルス由来蛋白はペプチド免疫療法の有力な標的候補となり得る。本稿では，我々の今までの研究の中から，EBウイルス由来蛋白LMP1のpromiscuousヘルパーT細胞エピトープ同定に関する研究を紹介する。また，本疾患に対して，エピトープペプチドにToll様受容体リガンドをアジュバントとして組み合わせた免疫療法の可能性や，抗programmed death-1/programmed death-ligand 1抗体の併用治療に関して，我々の研究結果を中心に概説する。

DOI： 10.5648/jjiao.36.15

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

PD-1 is a co-repressive receptor that curbs T cell activation and thereby serves as a protection mechanism against autoimmunity under physiological conditions. Under pathological conditions, tumor cells express PD-L1 as an adaptive resistant mechanism to suppress PD-1+ T cells to evade host immunosurveillance. PD-1 therefore is a key target in cancer immunotherapy. Despite the extensive studies of PD-1 expression regulation, the pdcd1 transcription machinery and regulatory mechanisms are still not fully understood. We report here that the NF-κB p50 homodimer is a transcription regulator of PD-1 in activated T cells. A putative κB sequence exists at the pdcd1 promoter. All five NF-κB Rel subunits are activated in activated T cells. However, only the p50 homodimer directly binds to the κB sequence at the pccd1 promoter in CD4+ and CD8+ T cells. Deficiency in p50 results in reduced PD-1 expression in both CD4+ and CD8+ T cells in vitro. Using an in vivo mixed bone marrow chimera mouse model, we show that p50 regulates PD-1 expression in a cell-intrinsic way and p50 deficiency leads to decreased PD-1 expression in both antigen-specific CD4+ and CD8+ T cells in vivo. The expression levels of H3K4me3-specific histone methyltransferase increased significantly, resulting in a significant increase in H3K4me3 deposition at the pdcd1 promoter in activated CD4+ and CD8+ T cells. Inhibition of H3K4me3 significantly decreased p50 binding to the pdcd1 promoter and PD-1 expression in a T cell line. Our findings determine that the p50-H3K4me3 axis regulates pdcd1 transcription activation in activated T cells.

DOI： 10.1080/2162402X.2018.1483302

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Inhibition of specific Akt isoforms in CD8+ T cells promotes favored differentiation into memory versus effector cells, the former of which are superior in mediating antitumor immunity. In this study, we investigated the role of upstream PI3K isoforms in CD8+ T-cell differentiation and assessed the potential use of PI3K isoform-specific inhibitors to favorably condition CD8+ T cells for adoptive cell therapy. The phenotype and proliferative ability of tumor antigen-specific CD8+ T cells was assessed in the presence of PI3K-α, -β, or -δ inhibitors. Inhibition of PI3K-δ, but not PI3K-α or PI3K-β, delayed terminal differentiation of CD8+ T cells and maintained the memory phenotype, thus enhancing their proliferative ability and survival while maintaining their cytokine and granzyme B production ability. This effect was preserved in vivo after ex vivo PI3K-δ inhibition in CD8+ T cells destined for adoptive transfer, enhancing their survival and also the antitumor therapeutic activity of a tumor-specific peptide vaccine. Our results outline a mechanism by which inhibitions of a single PI3K isoform can enhance the proliferative potential, function, and survival of CD8+ T cells, with potential clinical implications for adoptive cell transfer and vaccine-based immunotherapies. Cancer Res; 77(15); 4135-45. ©2017 AACR.

DOI： 10.1158/0008-5472.CAN-16-1925

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recent advances in cancer immunology, such as the discovery of immune checkpoint inhibitors, have validated immune cells as potential key players for effective cancer treatment. The efficacy of these therapies seems to be codependent on a tumor-reactive T lymphocyte response. For many years, numerous attempts and strategies in developing vaccines to generate tumor-reactive T cells have yielded poor results in the clinic due to suboptimal immunogenicity and the inability to overcome an immunosuppressive tumor microenvironment. In this review, we summarize past and current advances in T cell vaccines and describe our experience in developing optimized methods for antigen/adjuvant selection and vaccine administration in order to induce powerful anti-tumor responses.

DOI： 10.1016/j.coi.2017.07.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nasal natural killer/T-cell lymphoma (NNKTL) is an aggressive neoplasm with poor therapeutic responses and prognosis. The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) pathway plays an important role in immune evasion of tumor cells through T-cell exhaustion. The aim of the present study was to examine the expression of PD-L1 and PD-1 molecules in NNKTL. We detected the expression of PD-L1 in biopsy samples from all of the NNKTL patients studied. PD-L1 was found on both malignant cells and tumor-infiltrating macrophages, while PD-1-positive mononuclear cells infiltrated the tumor tissues in 36% of patients. Most significantly, soluble PD-L1 (sPD-L1) was present in sera of NNKTL patients at higher levels as compared to healthy individuals and the levels of serum sPD-L1 in patients positively correlated with the expression of PD-L1 in lymphoma cells of tumor tissues. In addition, the high-sPD-L1 group of patients showed significantly worse prognosis than the low-sPD-L1 group. Furthermore, we confirmed that membrane and soluble PD-L1 was expressed on the surface and in the culture supernatant, respectively, of NNKTL cell lines. The expression of PD-L1 was observed in tumor tissues and sera from a murine xenograft model inoculated with an NNKTL cell line. Our results suggest that sPD-L1 could be a prognostic predictor for NNKTL and open up the possibility of immunotherapy of this lymphoma using PD-1/PD-L1 axis inhibitors.

DOI： 10.1007/s00262-017-1987-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Stimulator of IFN genes (STING) spontaneously contributes to anti-tumor immunity by inducing type I interferons (IFNs) following sensing of tumor-derived genomic DNAs in the tumor-bearing host. Although direct injection of STING ligands such as cyclic diguanylate monophosphate (c-di-GMP) and cyclic [G(2',5')pA(3',5')p] (cGAMP) into the tumor microenvironment exerts anti-tumor effects through strong induction of type I IFNs and activation of innate and adaptive immunity, the precise events caused by STING in the tumor microenvironment remain to be elucidated. We describe here our finding that a CD45+ CD11bmid Ly6C+ cell subset transiently accumulated in mouse tumor microenvironment of 4T1 breast cancer, squamous cell carcinomas, CT26 colon cancer, or B16F10 melanoma tissue after intratumoral injection of cGAMP. The accumulated cells displayed a macrophage (M ) phenotype since the cells were positive for F4/80 and MHC class II and negative for Ly6G. Intratumoral cGAMP treatment did not induce Mφ accumulation in STING-deficient mice. Depletion of CD8+ T cell using anti-CD8 mAb impaired the anti-tumor effects of cGAMP treatment. Depletion of the Mφ using clodronate liposomes impaired the anti-tumor effects of cGAMP treatment. Functional analysis indicated that the STING-triggered tumor-migrating Mφ exhibited phagocytic activity, production of tumor necrosis factor alpha TNFα), and high expression levels of T cell-recruiting chemokines, Cxcl10 and Cxcl11, IFN-induced molecules, MX dynamin-like GTPase 1 (Mx1) and 2'-5' oligoadenylate synthetase-like 1 (Oasl1), nitric oxide synthase 2 (Nos2), and interferon beta 1 (Ifnb1). These results indicate that the STING-triggered tumor-migrating Mφ participate in the anti-tumor effects of STING-activating compounds.

DOI： 10.1007/s00262-017-1975-1

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記述言語：英語   出版者・発行元：日本がん免疫学会  

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Synthetic peptide vaccines aim to elicit and expand tumor-specific T cells capable of controlling or eradicating the tumor. Despite the high expectations based on preclinical studies, the results of clinical trials using peptide vaccines have been disappointing. Thus, many researchers in the field have considered peptide vaccines as outdated and no longer viable for cancer therapy. However, recent progress in understanding the critical roles of immune adjuvants, modes of vaccine administration and T cell dynamics has lead to a rebirth of this approach and reconsidering the use of peptide vaccines for treating malignant disorders.

DOI： 10.1016/j.coi.2016.11.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The design of efficacious and cost-effective therapeutic vaccines against cancer remains both a research priority and a challenge. For more than a decade, our laboratory has been involved in the development of synthetic peptide-based anti-cancer therapeutic vaccines. We first dedicated our efforts in the identification and validation of peptide epitopes for both CD8 and CD4 T cells from tumor-associated antigens (TAAs). Because of suboptimal immune responses and lack of therapeutic benefit of peptide vaccines containing these epitopes, we have focused our recent efforts in optimizing peptide vaccinations in mouse tumor models using numerous TAA epitopes. In this focused research review, we describe how after taking lessons from the immune system's way of dealing with acute viral infections, we have designed peptide vaccination strategies capable of generating very high numbers of therapeutically effective CD8 T cells. We also discuss some of the remaining challenges to translate these findings into the clinical setting.

DOI： 10.1007/s00262-016-1834-5

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Substantial evidence indicates that immunotherapy is a feasible and effective approach for the treatment of numerous types of cancer. Among various immunotherapy options, peptide vaccines to generate antitumor T cells appear as promising candidates, because of their cost effectiveness and ease of implementation. Nevertheless, most peptide vaccines are notorious for being weekly immunogenic and, thus, optimization of the vaccination strategy is essential to achieve therapeutic effectiveness. In addition, effective peptide vaccines must stimulate both CD8 cytotoxic and CD4 helper T lymphocytes. Our group has been successful in designing effective peptide vaccination strategies for inducing CD8 T-cell responses in mouse tumor models. Here, we describe a somewhat similar, but distinct, peptide vaccination strategy capable of generating vast CD4 T-cell responses by combining synthetic peptides with toll-like receptor (TLR) agonists and OX40/CD40 costimulation. This vaccination strategy was efficient in overcoming immune tolerance to a self-tumor-associated antigen and generated significant antitumor effects in a mouse model of malignant melanoma. The optimized peptide vaccine also allowed the expansion of adoptively transferred CD4 T cells without the need for lymphodepletion and IL2 administration, generating effective antimelanoma responses through the enhancement of proliferative and antiapoptotic activities of CD4 T cells. These results have practical implications in the design of more effective T-cell-based immunotherapies. Cancer Immunol Res; 5(1); 72-83. ©2016 AACR.

DOI： 10.1158/2326-6066.CIR-16-0194

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1189/jlb.3CE0216-091R

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tumor immune escape has been a major problem for developing effective immunotherapy. The human leukocyte antigen G (HLA-G) is a non-classical MHC class I molecule whose primary function is to protect the fetus from the mother's immune system. While HLA-G is hardly found in normal adult tissues, various tumor cells are known to express it, aiding their escape from the immune system. Thus, HLA-G is an attractive immunotherapy target. CD4(+) helper T lymphocytes (HTLs) play an important role in the immune reaction against tumors by assisting in the generation and persistence of CD8(+) cytotoxic T lymphocytes (CTLs) or by displaying direct antitumor effects. We report here that HLA-G expression in breast cancer significantly correlates with a poor prognosis. Also, we describe that the MHC class II-binding peptide HLA-G26-40 was effective in eliciting tumor-reactive CD4(+) T cell responses. Furthermore, treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine increased HLA-G expression in tumors and subsequently enhanced recognition by HLA-G26-40-specific HTLs. These findings predict that a combination immunotherapy targeting HLA-G together with a DNA methyltransferase inhibitor could be useful against some cancers.

DOI： 10.1080/2162402X.2016.1169356

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その他リンク： http://amcor.asahikawa-med.ac.jp/modules/xoonips/detail.php?id=27471649

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The success of adoptive T cell-based immunotherapy (ACT) in cancer is limited in part by the accumulation of myeloid-derived suppressor cells (MDSC), which block several T cell functions, including T cell proliferation and the expression of various cytotoxic mediators. Paradoxically, the inhibition of CD8+ T cell differentiation into cytotoxic populations increased their efficacy after ACT into tumor-bearing hosts. Therefore, we aimed to test the impact of conditioning CD8+ T cells with MDSC on their differentiation potential and ACT efficacy. Our results indicate that MDSC impaired the progression of CD8+ T cells into effector populations, without altering their activation status, production of IL-2, or signaling through the T cell receptor. In addition, culture of CD8+ T cells with MDSC resulted in an increased ACT anti-tumor efficacy, which correlated with a higher frequency of the transferred T cells and elevated IFNγ production. Interestingly, activated CD62L+ CD8+ T cells were responsible for the enhanced anti-tumor activity showed by MDSC-exposed T cells. Additional results showed a decreased protein synthesis rate and lower activity of the mammalian/mechanistic target of rapamycin (mTOR) in T cells conditioned with MDSC. Silencing of the negative mTOR regulator tuberous sclerosis complex-2 in T cells co-cultured with MDSC restored mTOR activity, but resulted in T cell apoptosis. These results indicate that conditioning of T cells with MDSC induces stress survival pathways mediated by a blunted mTOR signaling, which regulated T cell differentiation and ACT efficacy. Continuation of this research will enable the development of better strategies to increase ACT responses in cancer.

DOI： 10.18632/oncotarget.8197

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Epidermal growth factor receptor (EGFR)-targeted therapy has been widely accepted as a promising treatment for solid tumors. Steroid treatment is used to prevent adverse effect of anti-EGFR antibody; however, influence of steroids in the antitumor activity of targeted antibody remains poorly understood. Herein, we demonstrated the impact of steroids in induced antibody-dependent cellular cytotoxicity (ADCC) activity of natural killer (NK) cells by cetuximab. METHODS: Various numbers of NK cells from healthy donors were co-cultured with tumor and/or cetuximab with or without dexamethasone. After incubation, NK cells, ADCC activity, survival, and activation markers expression were determined. RESULTS: Clinical concentration of dexamethasone treatment clearly inhibited cetuximab-induced ADCC activity of NK cells against head and neck squamous cell carcinoma (HNSCC) and colon cancer. Dexamethasone decreased the activation marker CD69 expression on NK cells. CONCLUSION: This is the first report that shows the negative affect of steroids in cancer treatment using therapeutic antibody. Attention needs to be paid for using steroids in tumor treatment.

DOI： 10.1002/hed.23906

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Extranodal natural killer/T-cell lymphoma, nasal type (NKTL) is a rare but highly aggressive Epstein-Barr virus-related malignancy, which mainly occurs in nasopharyngeal and nasal/paranasal areas. In addition to its high prevalence in Asian, Central American and South American populations, its incidence rate has been gradually increasing in Western countries. The current mainstay of treatment is a combination of multiple chemotherapies and irradiation. Although chemoradiotherapy can cure NKTL, it often causes severe and fatal adverse events. Because a growing body of evidence suggests that immunotherapy is effective against hematological malignancies, this treatment could provide an alternative to chemoradiotherapy for treatment of NKTL. In this review, we focus on how recent findings could be used to develop efficient immunotherapies against NKTL.

DOI： 10.2217/imt.15.103

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その他リンク： http://amcor.asahikawa-med.ac.jp/modules/xoonips/detail.php?id=26642249

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

HER-3 expression has been reported to act as an important oncoprotein in head and neck squamous cell carcinoma. This protein is known to control tumor proliferation and acquisition of resistance by tumor cells towards EGFR inhibitors, therefore, development of a HER-3-targeted therapy is desirable. In this study, we found that HER-3 expression on tumor cells was increased after EGFR inhibition. To establish a novel therapeutic approach for HER-3-positive head and neck carcinoma, we identified a HER-3 helper epitope that could elicit effective helper T cell responses to the naturally processed HER-3-derived epitope presented in a HER-3 expressing tumors. This epitope induced potent cytolytic activity of CD4 T cells against such tumor cells. Moreover, pan HER-family tyrosine kinase inhibitor augmented the responses of HER-3-reactive CD4 T cells via upregulation of HLA-DR protein on the surface of tumor cells. Our results supports the validity of CD4 T cell-dependent HER-3-targeted therapy combined with a broad inhibitor of HER-family.

DOI： 10.1038/srep16280

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その他リンク： https://www.nature.com/articles/srep16280

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nasal natural killer/T-cell lymphoma (NNKTL) is associated with Epstein-Barr virus and has a poor prognosis because of local invasion and/or multiple dissemination. Various chemokines play a role in tumor proliferation and invasion, and chemokine receptors including the C-C chemokine receptor 4 (CCR4) are recognized as potential targets for treating hematologic malignancies. The aim of the present study was to determine whether specific chemokines are produced by NNKTL. We compared chemokine expression patterns in culture supernatants of NNKTL cell lines with those of other lymphoma or leukemia cell lines using chemokine protein array and ELISA. Chemokine (C-C motif) ligand (CCL) 17 and CCL22 were highly produced by NNKTL cell lines as compared to the other cell lines. In addition, CCL17 and CCL22 were readily observed in the sera of NNKTL patients. The levels of these chemokines were significantly higher in patients than in healthy controls. Furthermore, we detected the expression of CCR4 (the receptor for CCL17 and CCL22) on the surface of NNKTL cell lines and in tissues of NNKTL patients. Anti-CCR4 monoclonal antibody (mAb) efficiently induced antibody-dependent cellular cytotoxicity mediated by natural killer cells against NNKTL cell lines. Our results suggest that CCL17 and CCL22 may be important factors in the development of NNKTL and open up the possibility of immunotherapy of this lymphoma using anti-CCR4 mAb.

DOI： 10.1007/s00262-015-1675-7

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その他リンク： http://link.springer.com/content/pdf/10.1007/s00262-015-1675-7.pdf

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: The expression of c-Met and its ligand HGF plays a critical role in cell proliferation and is involved in numerous malignancies. Because c-Met expression and its role in NK/T-cell lymphoma remain unclear, we studied the expression and function of c-Met in NK/T-cell lymphoma cells. In addition, we investigated the possibility that c-Met could function as a tumor-associated antigen for helper T lymphocytes (HTLs). Methods: We evaluated whether HGF and c-Met were expressed in NK/T-cell lymphoma and the capacity of predicted c-Met HTL epitopes to induce antitumor responses in vitro. In addition, c-Met inhibitor was evaluated for the ability to inhibit TGF-β production in tumor and subsequently increase HTL recognition. Results: c-Met and HGF were expressed in NK/T-cell lymphoma cell lines, nasal NK/T-cell lymphoma specimens and patient serum samples. Moreover, HGF was shown to promote NK/T cell lymphoma (NKTCL) proliferation in an autocrine manner. Furthermore, we have identified three novel c-Met HTL epitopes that were restricted by several HLA-DR molecules. Notably, peptide-induced HTL lines directly recognized and killed c-Met expressing NK/T-cell lymphomas and various epithelial solid tumors. The c-Met specific HTLs could also recognize dendritic cells (DCs) pulsed with c-Met expressing tumor cell lysates. In addition, we observed that c-Met inhibition augmented HTL recognition by decreasing TGF-β production by tumor cells. Lastly, autophagy partly regulated the HTL responses against tumors. Conclusions: We identified novel c-Met HTL epitopes that can elicit effective antitumor responses against tumors expressing c-Met. Our results provide the rationale of combining c-Met targeting therapy and immunotherapy for NKTCLs and epithelial tumors.

DOI： 10.4161/2162402X.2014.976077

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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その他リンク： http://amcor.asahikawa-med.ac.jp/modules/xoonips/detail.php?id=2015169489

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: EGFR-targeted therapy is an attractive option for head and neck squamous cell carcinoma patients. We have recently reported the use of EGFR inhibitors as an adjunct treatment to enhance HLA-DR expression in tumor cells to improve cancer immunotherapy. Nevertheless, we observed that EGFR inhibitors resulted in decreased anti-tumor responses, regardless of upregulation of HLA-DR expression on the tumor cell. In this study, we specifically investigated the mechanisms by which EGFR inhibition modulated anti-tumor responses. METHODS: An EGFR inhibitor erlotinib was used to assess the modulation of anti-tumor responses by tumor antigen-specific helper T cells. We then examined whether administration of the EGFR inhibitor altered tumor cytokine profiles and expression of immune-related molecules on tumor cells. RESULTS: Despite the augmented HLA-DR expression on a gingival cancer cell line by EGFR inhibition, anti-tumor responses of EGFR reactive helper T cell clones against tumor cells were decreased. EGFR inhibition did not change the expression of CD80, CD86, or PD-L1 on the tumor cells. Conversely, production of transforming growth factor beta (TGF-β) and prostaglandin E2 was increased by EGFR inhibition, indicating that these immunosuppressive molecules were involved in diminishing tumor recognition by T cells. Significantly, attenuation of HTL responses against tumors after EGFR inhibition was reversed by the addition of anti-TGF-β antibody or COX2 inhibitors. CONCLUSIONS: Targeting TGF-β and prostaglandin E2 may allow for improved outcomes for cancer patients treated with combination immunotherapy and EGFR inhibitors.

DOI： 10.1186/s12967-014-0265-3

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Posttranslational modifications regulate the function and stability of proteins, and the immune system is able to recognize some of these modifications. Therefore, the presence of posttranslational modifications increases the diversity of potential immune responses to a determinant antigen. The stimulation of tumor-specific CD4(+) helper T lymphocytes (HTLs) is considered important for the production of anti-tumor antibodies by B cells and for the generation and persistence of CD8(+) cytotoxic T lymphocytes, and in some instances, HTLs can directly reduce tumor cell growth. Identification of MHC class II-restricted peptide epitopes from tumor-associated antigens including those generated from posttranslational protein modifications should enable the improvement of peptide-based cancer immunotherapy. We describe here an MHC class II binding peptide from the tumor protein p53, which possesses an acetylated lysine at position 120 (p53110-124/AcK120) that is effective in eliciting CD4(+) T cell responses specific for the acetylated peptide. Most importantly, the acetylated peptide-reactive CD4 HTLs recognized the corresponding naturally processed posttranslational modified epitope presented by either dendritic cells loaded with tumor cell lysates or directly on tumors expressing p53 and the restricting MHC class II molecules. Treatment of tumor cells with a histone deacetylase inhibitor augmented their recognition by the p53110-124/AcK120-reactive CD4(+) T cells. These findings prove that the epitope p53110-124/AcK120 is immunogenic for anti-tumor responses and is likely to be useful for cancer immunotherapy.

DOI： 10.1007/s00262-014-1533-z

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

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その他リンク： http://amcor.asahikawa-med.ac.jp/modules/xoonips/detail.php?id=2014228829

担当区分：筆頭著者   記述言語：日本語   出版者・発行元：日本耳鼻咽喉科免疫アレルギー学会  

近年，癌治療における新たな戦略としてキラーT 細胞を標的としたペプチドワクチンや樹状細胞療法，遺伝子改変T 細胞療法といった獲得免疫による免疫療法がさまざまな癌腫に対して試みられてきたが，その成果はいまだ満足できる水準に達していない。癌免疫治療による治療効果の更なる改善を目指して多岐にわたる基礎研究が行われており，腫瘍による免疫抑制機構の解明と克服や，より有効な抗腫瘍免疫を惹起しうるアジュバントの開発がその主眼となっている。我々は頭頸部扁平上皮癌の腫瘍抗原としてEGFR （Epidermal Growth Factor Receptor） に着目し，EGFR タンパク由来のペプチド抗原が腫瘍抗原特異的なヘルパーT 細胞を誘導し，抗腫瘍効果を発揮できることを明らかにしてきた。本稿では腫瘍免疫を取り巻く現状を，ヘルパーT 細胞エピトープやEGFR 阻害薬などの分子標的薬を含めた免疫アジュバントを中心にコンビネーションセラピーの可能性を含めて概説する。

DOI： 10.5648/jjiao.32.185

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その他リンク： http://amcor.asahikawa-med.ac.jp/modules/xoonips/detail.php?id=20141225

担当区分：筆頭著者   掲載種別：研究論文（学術雑誌）  

Background:Head and neck squamous cell carcinoma (HNSCC) is a major cause of cancer-related morbidity and mortality worldwide. Epidermal growth factor receptor (EGFR)-targeted therapy is an attractive strategy alternative to conventional cancer treatments for HNSCC, but its efficacy remains controversial. T-cell-based immunotherapy has been proposed as a novel therapeutic approach to improve the clinical outcome for HNSCC. In this study, we report human epidermal receptor (HER) family epitopes that induced CD4 T-cell responses to HNSCC. The results provide support for a novel strategy to treat HNSCC by combining EGFR-targeted therapy with T-cell-based immunotherapy. Methods:We evaluated the capacity of predicted CD4 T-cell peptide epitopes from EGFR to induce antitumour immune responses in vitro. In addition, EGFR inhibitors were evaluated for their ability to augment tumour MHC class II expression in HNSCC cell lines and subsequently increase T-cell recognition.Results:Among several predicted peptide epitopes, EGFR 875-889 elicited CD4 T-cell responses that were restricted by HLA-DR4, DR15, or DR53 molecules, indicating that the peptide functions as a promiscuous T-cell epitope. The peptide-reactive T cells responded to autologous dendritic cells loaded with EGFR-expressing tumour cell lysates, indicating that these epitopes are naturally processed. In addition, the CD4 T cells were capable of directly recognising and killing HNSCC cells expressing EGFR and the appropriate HLA class II molecule. T cells reactive with the EGFR 875-889 epitope could be detected in the blood of HNSCC patients. EGFR 875-889 -reactive CD4 T cells were also able to recognise several peptide analogues derived from homologous regions of EGFR family members, HER-2, HER-3 and c-MET. Finally, we examined the effects of EGFR tyrosine kinase inhibition or EGFR-blocking antibodies on CD4 T-cell tumour reactivity. Treatment of tumour cells with the EGFR inhibitors enhanced tumour recognition by EGFR 875-889 -reactive T cells presumably due to the upregulation of HLA-DR expression in the HNSCC cells.Conclusion:We identified novel CD4 T-cell EGFR epitopes and amongst these, EGFR 875-889 functions as a promiscuous helper T-cell epitope that can elicit effective antitumour T-cell responses against tumours expressing HER family members and c-MET. These observations should facilitate the translation of T-cell-based immunotherapy into the clinic for the treatment of HNSCC and provide a rational basis for EGFR inhibition, immune-targeted combination therapy. © 2013 Cancer Research UK. All rights reserved.

DOI： 10.1038/bjc.2013.577

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：耳鼻咽喉科臨床学会  

DOI： 10.5631/jibirin.106.423

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その他リンク： http://id.ndl.go.jp/bib/024650788

記述言語：日本語   出版者・発行元：耳鼻咽喉科展望会  

DOI： 10.11453/orltokyo.56.128

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Human T cell leukemia virus type 1 (HTLV-1) induced adult T cell leukemia/lymphoma (ATLL) is usually a fatal lymphoproliferative malignant disease. Thus, the enhancement of T cell immunity to ATLL through the development of therapeutic vaccines using characterized T cell peptide epitopes could be of value. We isolated and characterized HLA-DR-bound peptides from HTLV-1-transformed T cells by fractionating on reverse-phase high performance liquid chromatography and Edman NH(2)-terminal sequencing and were able to identify five independent peptide sequences. One of the identified peptide sequences corresponded to a fragment of the human interleukin-9 receptor alpha (IL-9Rα), which is commonly expressed by HTLV-1-infected T cell lymphoma cells. Using a synthetic peptide corresponding to the identified IL-9Rα sequence, we generated antigen-specific CD4 helper T lymphocytes in vitro, which were restricted by HLA-DR15 or HLA-DR53 molecules and could recognize and kill HTLV-1+, IL-9Rα+ T cell lymphoma cells. These results indicate that IL-9Rα functions as T cell leukemia/lymphoma-associated antigen for CD4 T cells and that synthetic peptides such as the one described here could be used for T cell-based immunotherapy against IL-9Rα positive ATLL.

DOI： 10.1007/s00262-012-1284-7

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：耳鼻咽喉科臨床学会  

DOI： 10.5631/jibirin.105.277

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その他リンク： http://id.ndl.go.jp/bib/023577759

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: T-cell based immunotherapy for lung cancer (LC) could be a promising and novel therapeutic approach. Six-transmembrane epithelial antigen of the prostate (STEAP) and the polycomb group protein enhancer of zeste homolog 2 (EZH2) are highly expressed in LC and since the expression of molecules in normal tissue is significantly lower as compared to tumor cells, these proteins are considered as potential tumor-associated antigens (TAAs) for developing T-cell based immunotherapy. METHODS: We assessed the capacity of predicted CD4 T-cell epitopes from STEAP and EZH2 to induce anti-tumor immune responses to LC cell lines. RESULTS: Out of several predicted epitopes, two synthetic peptides, STEAP281-296 and EZH295-109, were effective in inducing CD4 T-cell responses that were restricted by HLA-DR1, DR15, or DR53 molecules, indicating that the peptides function as promiscuous T-cell epitopes. Moreover, STEAP281-296 and EZH295-109-reactive T-cells could directly recognize STEAP or EZH2 expressing LC cells in an HLA-DR restricted manner. In addition, some STEAP-reactive T-cells responded to STEAP+ tumor cell lysates presented by autologous dendric cells. Most significantly, both of these peptides were capable of stimulating in vitro T-cell responses in patients with LC. CONCLUSIONS: Peptides STEAP281-296 and EZH295-109 function as strong CD4 T-cell epitopes that can elicit effective anti-tumor T-cell responses against STEAP or EZH2 expressing LC. These observations may facilitate the translation of T-cell based immunotherapy into the clinic for the treatment of LC.

DOI： 10.1186/1479-5876-9-191

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We investigated the relationship between nasopharyngeal flora of pediatric patients and antibiotic consumption in a local community in Japan between 2000 and 2009 retrospectively. There was a clear relationship between the lower annual consumption rate of cephalosporins and the lower annual prevalence of non-susceptible strains of Streptococcus pneumoniae (SP). High prevalence of BLNAR (β-lactamase nonproducing ampicillin-resistant Haemophilus influenzae) has been one of the bacteriological features of Japan.

DOI： 10.1159/000324789

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記述言語：英語   著書種別：学術書

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総ページ数：xii, 234 p.   記述言語：英語  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：全日本病院出版会  

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担当区分：筆頭著者,　責任著者   記述言語：日本語   出版者・発行元：東京 : 先端医学社  

扁桃病巣疾患は扁桃を病巣としてほかの臓器に障害をきたす疾患群の総称であり、扁桃摘出術が奏効する。その病態が感染症ではなく扁桃を病巣とした自己免疫的・自己炎症的機序と明らかになってきたことから、最近では病巣感染症よりも扁桃病巣疾患もしくはTIASとよばれるようになった。本疾患群にはIgA腎症や掌蹠膿疱症、胸肋鎖骨過形成症、PFAPA症候群といったさまざまな難治性疾患が含まれている。本稿では、本疾患の歴史およびこれまで解明されてきた病態について概説する。(著者抄録)

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その他リンク： https://ndlsearch.ndl.go.jp/books/R000000004-I032538138

担当区分：筆頭著者,　最終著者,　責任著者   記述言語：日本語   出版者・発行元：(有)科学評論社  

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担当区分：筆頭著者,　最終著者,　責任著者   記述言語：日本語   出版者・発行元：東京 : 日本臨床社  

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その他リンク： https://ndlsearch.ndl.go.jp/books/R000000004-I031577955

担当区分：最終著者   記述言語：日本語   出版者・発行元：東京 : 日本臨床社  

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その他リンク： https://ndlsearch.ndl.go.jp/books/R000000004-I031577939

担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：日本臨床社  

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記述言語：日本語   出版者・発行元：大阪 : 医薬ジャーナル社  

DOI： 10.20837/3201806748

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その他リンク： https://ndlsearch.ndl.go.jp/books/R000000004-I029070594

担当区分：最終著者   記述言語：日本語   出版者・発行元：(株)全日本病院出版会  

扁桃病巣疾患とは扁桃を病巣として他の臓器に障害をきたす疾患群の総称であり、扁桃摘出術が奏効する。扁桃病巣疾患は急性扁桃炎を含む急性上気道炎時に悪化することから扁桃病巣感染症としても知られているが、扁桃における自己免疫の活性化がその病態の機序として明らかになったため、近年では扁桃病巣疾患と呼ばれている。代表的疾患としてIgA腎症、掌蹠膿疱症、胸肋鎖骨過形成症(SAPHO症候群)、PFAPA症候群があり、扁桃摘出術(扁摘)の極めて高い有効性が報告されている。他に、尋常性乾癬、膿疱性乾癬、滴状乾癬、結節性紅斑、IgA血管炎などの皮膚疾患、慢性関節リウマチ、反応性関節炎などの骨関節疾患、加えてベーチェット病や炎症性腸疾患などの中には扁摘が著効を呈した症例も数多く報告されている。扁桃摘出術は耳鼻咽喉科医にとって初歩的な手術であり、積極的に手術を勧めることが求められる。(著者抄録)

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担当区分：筆頭著者,　最終著者,　責任著者   記述言語：日本語   出版者・発行元：(有)科学評論社  

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担当区分：責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：全日本病院出版会  

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：株式会社医学書院  

鼻性NK/T細胞リンパ腫は鼻腔や咽頭に初発し,顔面正中部に沿って進行する破壊性のNK細胞もしくはγδT細胞由来の悪性リンパ腫である。不明熱やウイルス関連血液貪食症候群といった全身症状の合併を認める場合がある。鼻性NK/T細胞リンパ腫はEBウイルス関連疾患であり,EBウイルス潜伏感染2型を呈する。EBウイルス蛋白であるLMP1が,ケモカインやマイクロRNAを介して腫瘍の増殖や生存に寄与している。本疾患の診断には,CD56の免疫組織染色やin situハイブリダイゼーション法によるEBER染色が有用である。EBウイルスDNAは診断および病勢,予後を反映する鋭敏な腫瘍マーカーとなる。本疾患における治療の第一選択はMPVIC-P療法やDeVIC療法に代表される化学療法同時併用放射線治療であり,一定の効果が望まれる。今後の展望として,免疫療法や分子標的薬の臨床応用が期待される。(著者抄録)

DOI： 10.11477/mf.1411201432

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2017&ichushi_jid=J02122&link_issn=&doc_id=20171101160010&doc_link_id=10.11477%2Fmf.1411201432&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1411201432&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

担当区分：筆頭著者,　最終著者,　責任著者   記述言語：日本語   出版者・発行元：(株)東京医学社  

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担当区分：筆頭著者,　責任著者   記述言語：日本語   出版者・発行元：(株)Gakken  

扁桃病巣疾患の概念、掌蹠膿疱症や乾癬に対する扁摘の有効性、扁摘の安全性、扁桃を病巣とした掌蹠膿疱症の発症機序について概説した。これまでの報告によって、扁摘は掌蹠膿疱症に対してきわめて有効であり、扁摘以外の治療法よりも優れていることが示されている。また、掌蹠膿疱症の発症機序として、扁桃の常在菌に対する過剰免疫応答による扁桃B細胞の熱ショックタンパク質などに対する抗体産生と扁桃T細胞の掌蹠皮膚へのホーミングが関与している可能性が示唆されている。扁摘は安全な手術であり、掌蹠膿疱症に対する治療として医療経済的にもきわめて有効といえる。

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担当区分：筆頭著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：東京医学社  

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担当区分：筆頭著者,　責任著者   記述言語：日本語   出版者・発行元：(株)東京医学社  

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担当区分：筆頭著者,　最終著者,　責任著者   記述言語：日本語   出版者・発行元：(株)東京医学社  

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担当区分：最終著者   記述言語：日本語   出版者・発行元：(株)東京医学社  

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開催年月日： 2021年5月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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開催年月日： 2019年7月

記述言語：日本語   会議種別：口頭発表（招待・特別）  

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開催年月日： 2019年6月

記述言語：日本語   会議種別：口頭発表（一般）  

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開催年月日： 2019年4月

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2019年3月

記述言語：日本語  

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開催年月日： 2018年9月

記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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開催年月日： 2016年11月

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2016年11月

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2014年9月

記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（招待・特別）  

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開催年月日： 2013年10月

記述言語：英語   会議種別：口頭発表（一般）  

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開催年月日： 2013年6月

記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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開催年月日： 2012年9月

記述言語：英語   会議種別：口頭発表（一般）  

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会議種別：口頭発表（一般）  

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会議種別：シンポジウム・ワークショップ パネル（指名）  

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会議種別：シンポジウム・ワークショップ パネル（指名）  

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会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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会議種別：シンポジウム・ワークショップ パネル（指名）  

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会議種別：シンポジウム・ワークショップ パネル（指名）  

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会議種別：シンポジウム・ワークショップ パネル（指名）  

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会議種別：口頭発表（一般）  

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