Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00262-023-03460-0

researchmap

Other Link： https://link.springer.com/article/10.1007/s00262-023-03460-0/fulltext.html

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00262-023-03394-7

researchmap

Other Link： https://link.springer.com/article/10.1007/s00262-023-03394-7/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

Recent studies have shown that activation of the cGAS‐STING pathway is a key process in antitumor immune responses and various kinds of STING agonists have been developed for cancer immunotherapy. Despite promising preclinical studies, preliminary clinical results have shown only a modest effect of STING agonists. There is therefore a need to develop more effective treatment strategies. Based on previous observations that COX‐2 is frequently overexpressed not only in a variety of cancers but also in tumor myeloid cells and that it suppresses antitumor immunity and promotes tumor survival by producing PGE2, we investigated the antitumor effects of combination therapy with a STING agonist cGAMP and the selective COX‐2 inhibitor celecoxib in mouse models. Combination treatment with cGAMP and celecoxib inhibited tumor growth compared with either monotherapy, and the combination therapy induced both local and systemic antitumor immunity. cGAMP treatment decreased PD‐1 expression on tumor‐infiltrating T‐cells and enhanced T‐cell activation in tumor‐draining lymph nodes regardless of the presence of celecoxib. Meanwhile, although celecoxib treatment did not alter the frequency of CD4⁺CD25⁺Foxp3⁺ regulatory T‐cells, it enhanced the expression of costimulatory molecules and glycolysis‐associated genes in tumor‐infiltrating CD11b⁺Ly6G⁺ cells. Moreover, we also found that celecoxib decreased lactate efflux and increased the frequency of IFN‐γ‐ and TNF‐α‐producing CD8⁺ T‐cells in the tumor microenvironment. Taken together, our findings suggest that combined treatment with celecoxib may be an effective strategy to improve the antitumor efficacy of STING agonists.

DOI： 10.1002/ijc.34394

researchmap

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/ijc.34394

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

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 (HOXB7_8–25) 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

researchmap

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.15619

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

Neurokinin 2 receptor (NK2R), a G protein‐coupled receptor for neurokinin A (NKA), a tachykinin family member, regulates various physiological functions including pain response, relaxation of smooth muscle, dilation of blood vessels, and vascular permeability. However, the precise role and regulation of NK2R expression in cancer cells have not been fully elucidated. In this study, we found that high NK2R gene expression was correlated with the poor survival of colorectal cancer patients, and Interferon (IFN‐α/β) stimulation significantly enhanced NK2R gene expression level of colon cancer cells in a Janus kinas 1/2 (JAK 1/2)‐dependent manner. NKA stimulation augmented viability/proliferation and phosphorylation of Extracellular‐signal‐regulated kinase 1/2 (ERK1/2) levels of IFN‐α/β‐treated colon cancer cells and NK2R blockade by using a selective antagonist reduced the proliferation in vitro. Administration of an NK2R antagonist alone or combined with polyinosinic‐polycytidylic acid, a synthetic analog of double‐stranded RNA, to CT26‐bearing mice significantly suppressed tumorigenesis. NK2R‐overexpressing CT26 cells showed enhanced tumorigenesis and metastatic colonization in both lung and liver after the inoculation into mice. These findings indicate that IFN‐α/β‐mediated NK2R expression is related to the malignancy of colon cancer cells, suggesting that NK2R blockade may be a promising strategy for colon cancers.

DOI： 10.1111/cas.15397

researchmap

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.15397

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

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 TWIST1_140–162, 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

researchmap

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.15429

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.1080/2162402x.2021.2021619

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Rockefeller University Press  

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

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

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

researchmap

Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.14973

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00262-021-02940-5

researchmap

Other Link： https://link.springer.com/article/10.1007/s00262-021-02940-5/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Spandidos Publications  

DOI： 10.3892/ol.2021.12681

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00262-021-02864-0

researchmap

Other Link： https://link.springer.com/article/10.1007/s00262-021-02864-0/fulltext.html

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.1080/2162402x.2020.1856545

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

DOI： 10.5631/jibirin.113.787

researchmap

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.amjms.2020.03.012

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

DOI： 10.5631/jibirin.113.251

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00262-020-02524-9

researchmap

Other Link： http://link.springer.com/article/10.1007/s00262-020-02524-9/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.bbrc.2019.11.107

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.cellimm.2019.103925

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1186/s12967-019-1957-5

researchmap

Other Link： http://link.springer.com/article/10.1186/s12967-019-1957-5/fulltext.html

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1038/s41374-018-0182-9

researchmap

Other Link： http://www.nature.com/articles/s41374-018-0182-9

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.amjms.2019.01.005

researchmap

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00262-018-02294-5

researchmap

Other Link： http://link.springer.com/article/10.1007/s00262-018-02294-5/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.1080/2162402x.2018.1466771

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

DOI： 10.5631/jibirin.111.483

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

Pustulosis palmaris et plantaris (PPP) and pustulotic arthro‐osteitis (PAO) are tonsil‐related diseases. Treatment outcome of tonsillectomy and prognostic factors influencing the outcome have not been analyzed quantitatively. We evaluated those using the Palmoplantar Pustulosis Area and Severity Index (PPPASI). At 1, 3, 6, 12, 24 and more than 24 months post‐tonsillectomy, 20 (31%), 34 (48%), 70 (60%), 57 (80%), 36 (95%) and 23 (96%) patients realized 80% or more improvement of PPP skin lesions, respectively, and eight (17%), 23 (36%), 30 (50%), 38 (79%), 12 (100%) and four (100%) patients showed 80% or more improvement of PPPASI (i.e. PPPASI% ≥ 80%), respectively. At 1, 3, 6, 12 and more than 12 months post‐tonsillectomy, 19 (73%), 21 (66%), 27 (73%), 19 (79%) and 15 (83%) patients realized a disappearance of PAO‐induced arthralgia, respectively. Kaplan–Meier analysis of 80 patients with PPP revealed that, at 12 and 24 months post‐tonsillectomy, lesions disappeared (i.e. PPPASI = 0) in 38% and 66% of patients, respectively, and lesions improved by 80% or more (i.e. PPPASI% ≥ 80%) in 71% and 95% of patients, respectively. The log–rank test and univariate and multivariate analyses showed that smoking cessation post‐tonsillectomy and PAO were significant predictive factors for the early disappearance of skin lesions. This report is the first demonstrating objective evidence of the great efficacy of tonsillectomy to improve PPP skin lesions. Even post‐tonsillectomy, smoking inhibited the early disappearance of the lesions.

DOI： 10.1111/1346-8138.14348

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

DOI： 10.5631/jibirin.111.337

researchmap

Language：English   Publisher：日本癌学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.bbrc.2017.06.072

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Society for Head and Neck Surgery  

DOI： 10.5106/jjshns.27.45

researchmap

Language：English   Publisher：日本がん免疫学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.humimm.2017.02.004

researchmap

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00262-017-1987-x

researchmap

Other Link： http://link.springer.com/content/pdf/10.1007/s00262-017-1987-x.pdf

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00262-017-1975-1

researchmap

Other Link： http://link.springer.com/content/pdf/10.1007/s00262-017-1975-1.pdf

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

Nasal natural killer/T‐cell lymphoma (NNKTL) is an Epstein‐Barr virus (EBV)–associated malignancy and is characterized by local invasion and widespread dissemination, with a consequent poor prognosis. Micro‐RNAs (miRNAs) play roles in the pathogenesis of several malignancies by regulating gene expression and have been recently identified as stable entities in serum. Here, we investigated the value of circulating EBV‐miRNAs as biomarkers for NNKTL. Sera of patients with NNKTL were subjected to miRNA polymerase chain reaction (PCR)–array analysis, after which serum EBV‐miRNA levels were verified using quantitative PCR. The latter analysis revealed high miR‐BART2‐5p, miR‐BART7‐3p, miR‐BART13‐3p, and miR‐BART1‐5p expression levels in sera of patients with NNKTL and indicated accurate values for discriminating patients with NNKTL from healthy controls. Levels of these 4 EBV‐miRNAs, which were secreted from NNKTL cells, significantly decreased after treatment compared with those before treatment. Furthermore, a high circulating miR‐BART2‐5p level was associated with disease progression and poor prognosis in patients with NNKTL. Our findings demonstrate that circulating EBV‐miRNAs, particularly miR‐BART2‐5p, may serve as potential diagnostic and prognostic biomarkers in patients with NNKTL.

DOI： 10.1002/hon.2360

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Rhinologic Society  

DOI： 10.7248/jjrhi.55.169

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Society for Head and Neck Surgery  

DOI： 10.5106/jjshns.26.83

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.11374/shonijibi.37.58

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.1080/2162402x.2016.1169356

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

Nasal natural killer (NK)/T‐cell lymphoma (NNKTL) displays unusual clinicopathological features, and the prognosis is very poor, even in the early stages of the disease. For early stage NNKTL, we have developed a novel chemoradiotherapy regimen incorporating arterial infusion chemotherapy, administered via the superficial temporal artery, in combination with radiotherapy. The novel arterial infusion regimen consists of ifosfamide, carboplatin, methotrexate, peplomycin, and etoposide (MPVIC‐P). From 2003 to 2011, 12 patients with early stage NNKTL were treated with the MPVIC‐P regimen via arterial infusion with concomitant radiotherapy (54 Gy). We have previously reported on the presence of Epstein‐Barr virus (EBV) genetic DNA in NNKTL. Therefore, the effect of the treatment was evaluated by using both clinical findings and serum EBV DNA copy number. The observation period ranged from 39 months to 111 months post‐treatment (median: 81 months). All 12 patients achieved and maintained complete remission and, to date, show no sign of relapse. Serum EBV DNA copy numbers decreased to below detectable levels in all 12 patients tested. Manageable mucositis was the most common grade 3–4 toxicity, and it was seen in 10 (83%) patients. However, grade 3–4 hematological toxicity was only seen in 4 (33%) patients. We conclude that our regimen of intra‐maxillary arterial chemotherapy with concomitant radiotherapy is an effective treatment with minimal toxicity for early stage NNKTL. Copyright © 2015 John Wiley & Sons, Ltd.

DOI： 10.1002/hon.2273

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

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

researchmap

Other Link： https://www.nature.com/articles/srep16280.pdf

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00262-015-1675-7

researchmap

Other Link： http://link.springer.com/article/10.1007/s00262-015-1675-7/fulltext.html

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Association for Cancer Research (AACR)  

Abstract

Purpose: Epitope-based cancer vaccines capable of inducing CD8 T-cell responses to tumor-associated antigens (TAA) expressed by tumor cells have been considered as attractive alternatives for the treatment of some types of cancer. However, reliable TAAs have not been identified for most malignant diseases, limiting the development of epitope-based vaccines. Herein, we report that the combinatorial therapy of polyinosinic–polycytidylic acid (poly-IC) and antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody (mAb) can be implemented with good results for tumors where no known TAAs have been identified.

Experimental Design: Three cancer mouse models (melanoma, lung, and colon) were used to evaluate therapeutic efficacy and examine the immunologic mechanisms of the poly-IC/anti–PD-L1 mAb therapy.

Results: The combined administration of poly-IC and anti–PD-L1 mAb into tumor-bearing mice generated potent immune responses resulting in the complete eradication or remarkable reduction of tumor growth. In some instances, the poly-IC/anti–PD-L1 mAb therapy induced long-lasting protection against tumor rechallenges. The results indicate that CD8 T cells but not CD4 T cells or NK cells mediated the therapeutic efficacy of this combinatorial therapy. Experiments using genetically deficient mice indicate that the therapeutic efficacy of this combinatorial therapy depended in part by the participation of type-I IFN, whereas IFN-γ did not seem to play a major role.

Conclusions: The overall results suggest that immunotherapy consisting of the combination of poly-IC/anti–PD-L1 mAb could be a promising new approach for treating patients with cancer, especially those instances where no reliable TAAs are available as a therapeutic vaccine. Clin Cancer Res; 20(5); 1223–34. ©2014 AACR.

DOI： 10.1158/1078-0432.ccr-13-2781

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Nasal NK/T‐cell lymphoma (NNKTL) is an Epstein‐Barr virus (EBV)‐associated malignancy and has distinct clinical and histological features. However, its genetic features are hitherto unclear. MicroRNAs (miRNAs) play a crucial role in the pathogenesis of several malignancies via regulating gene expression. In this study, we investigated whether the specific microRNAs were related to the tumor behaviors in NNKTL. MiRNA array and Quantitative RT‐PCR analyses revealed that miR‐15a was expressed at a much lower level in NNKTL cells (SNK‐1, SNK‐6, and SNT‐8) than in normal peripheral NK cells and EBV‐negative NK cell line KHYG‐1. Quantitative PCR and western blot analyses showed that the expression of MYB and cyclin D1, which are validated targets of miR‐15a, was higher in NNKTL cells. Transfection of NNKTL cells (SNK‐6 and SNT‐8) with a miR‐15a precursor decreased MYB and cyclin D1 levels, thereby blocking G1/S transition and cell proliferation. Knockdown of EBV‐encoded latent membrane protein 1 (LMP1) significantly increased miR‐15a expression in SNK‐6 cells. In NNKTL tissues, we found that reduced miR‐15a expression, which correlated with MYB and cyclin D1 expression, was associated with poor prognosis of NNKTL patients. These data suggest that downregulation of miR‐15a, possibly due to LMP1, implicates in the pathogenesis of NNKTL by inducing cell proliferation via MYB and cyclin D1. Thus, miR‐15a could be a potential target for antitumor therapy and a prognostic predictor for NNKTL. Am. J. Hematol. 89:25–33, 2014. © 2013 Wiley Periodicals, Inc.

DOI： 10.1002/ajh.23570

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.exphem.2013.03.009

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

DOI： 10.5631/jibirin.106.447

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

DOI： 10.5631/jibirin.106.423

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

DOI： 10.5631/jibirin.106.329

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Summary

Nasal natural killer (NK)/T cell lymphoma (NNKTL) is associated with Epstein–Barr virus (EBV). The present study analysed gene expression patterns of the NNKTL cell lines SNK6, SNK1 and SNT8, which are positive for EBV and latent membrane protein (LMP)‐1, using a complementary DNA array analysis. We found that CD70 was specifically expressed in SNK6 and SNT8. Reverse transcription polymerase chain reaction and flow cytometric analyses confirmed that CD70 was expressed in all 3 NNKTL cell lines, but not in the other EBV‐positive NK‐cell lines. In vitro studies showed that NNKTL cell lines proliferated, in a dose‐dependent fashion, in response to exogenous soluble CD27, which is the ligand for CD70. In NNKTL patients, we confirmed that the CD70 was expressed on the lymphoma cells in NNKTL tissues and that soluble CD27 was present in sera at higher levels as compared to healthy individuals. Finally, complement‐dependent cytotoxicity assay showed that anti‐CD70 antibody mediated effective complement‐dependent killing of NNKTL cells and the affected target CD70 expression on the cells. These results suggest that CD70 acts as a functional receptor binding to soluble CD27, resulting in lymphoma progression and that immunotherapy using anti‐CD70 antibody may be a potential candidate for treatment for NNKTL.

DOI： 10.1111/bjh.12136

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

DOI： 10.5631/jibirin.105.747

researchmap

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.ijporl.2012.02.032

researchmap

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/art.34418

researchmap

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japan Society of Stomato-pharyngology  

A questionnaire for determineing tonsillectomy status in tonsil-related disease treatment was sent to university hospital dermatology, nephrology, and pediatrics departments in Japan. Among the 9.4% of subjects with pustulosis palmaris et plantaris (PPP) referred by dermatologists to otolaryngologists for possible tonsillectomy, 52.5% were actually treated by tonsillectomy, which 40% of the dermatology departments surveyed stated was effective. Of the 30.1% of those with IgA nephropathy referred by nephrologists and 12.0% referred by pediatricians, over 90% were treated by tonsillectomy. This treatment was stated to be effective by 90% of the nephrology departments and 70% of the pediatrics departments in over half of the subjects thus treated. Although results showed tonsillectomy to be widely accepted in effectively treating IgA nephropathy, many dermatologists seem to feel that the tonsils played only a small role in such cases. This means that education efforts about tonsillectomy effectiveness must be increased.

DOI： 10.14821/stomatopharyngology.25.61

CiNii Books

researchmap

Other Link： http://search.jamas.or.jp/link/ui/2012208248

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

DOI： 10.5631/jibirin.105.277

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

researchmap

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1111/j.1445-5994.2011.02594.x

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

Nasal natural killer (NK)/T‐cell lymphoma (NNKTL) is an Epstein‐Barr virus (EBV)‐related malignancy with poor prognosis and has distinct histological features characterized by angiocentric and polymorphous lymphoreticular infiltrates including inflammatory cells such as granulocytes, monocytes, macrophages and lymphocytes. Here, we show that the monocytes enhance proliferation as well as LMP1 expression of NNKTL cells by cell contact‐dependent interaction through membrane‐bound interleukin (IL)‐15. We used two EBV‐positive NK‐cell lines, SNK6 and KAI3, which originated from two patients—SNK6 from a patient with NNKTL and KAI3 from a patient with a severe mosquito allergy. We cocultured the cell lines with granulocytes or monocytes and examined whether proliferation, survival and LMP1 expression of the cells changed. Although cocultured granulocytes did not affect proliferation, survival or LMP1 expression of the cells, cocultured monocytes enhanced both proliferation and LMP1 expression in a dose‐dependent manner. These phenomena were not seen when monocytes were placed in a separate chamber. Moreover, the monocyte‐inducible proliferation and LMP1 expression were inhibited by treatment with an antibody against IL‐15. Furthermore, production of interferon‐gamma‐inducible protein (IP)‐10 were enhanced by coculture with monocytes and were inhibited by the antibody. Immunohistological studies confirmed that a number of infiltrating CD14‐positive monocytes contacted CD56‐positive lymphoma cells in all of 20 NNKTL tissues tested. These results suggest that monocytes enhance cell growth as well as LMP1 expression of NNKTL cells by cell contact‐dependent interaction through membrane‐bound IL‐15. In the microenvironment of NNKTL tissue, a positive feedback loop of interaction between lymphoma cells and monocytes may be present and contribute to lymphoma progression.

DOI： 10.1002/ijc.25969

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Spandidos Publications  

DOI： 10.3892/ijo.2011.949

researchmap

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.clineuro.2010.02.010

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cambridge University Press (CUP)  

Abstract

Objective:

We present the first reported case of primary small cell carcinoma of the lacrimal sac.

Case report:

A 67-year-old Japanese woman was referred to our department with a two-month history of left medial canthal swelling, epiphora and occasional nasal bleeding. Nasal endoscopy revealed a readily bleeding tumour in the left inferior meatus. Computed tomography and magnetic resonance imaging scans demonstrated that the tumour was mainly located in the left lacrimal sac. Histopathological studies of a biopsy specimen revealed small cell carcinoma. The patient was treated with four cycles of chemotherapy consisting of cisplatin and etoposide, in combination with radiotherapy. There was no evidence of recurrence or metastasis for five years.

Conclusion:

Small cell carcinoma originating in the head and neck region has been reported to be highly aggressive and to have a poor prognosis. We report a case of primary small cell carcinoma of the lacrimal sac successfully treated with chemo-radiotherapy.

DOI： 10.1017/s0022215110000940

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00262-010-0826-0

researchmap

Other Link： http://link.springer.com/article/10.1007/s00262-010-0826-0/fulltext.html

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

DOI： 10.5631/jibirin.102.1033

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Association for Cancer Research (AACR)  

Abstract

Purpose: Nasal natural killer (NK)/T-cell lymphoma is associated with Epstein-Barr virus and has poor prognosis because of local invasion and/or multiple dissemination. Recently, the role of chemokines/chemokine receptors in tumor proliferation and invasion has been shown. In this study, we examined whether the specific chemokines were related to the tumor behaviors in nasal NK/T-cell lymphoma.

Experimental Design: A chemokine protein array was used to examine specific chemokines produced by SNK-6 and SNT-8 (Epstein-Barr viruspositive nasal NK/T-cell lymphoma lines). The expression of interferon inducible protein 10 (IP-10) and the IP-10 receptor CXCR3 was investigated by ELISA and flow cytometry. Cell growth and invasion were assessed by the MTT and Matrigel invasion assays, respectively. Immunohistologic staining and ELISA were used to examine IP-10 expression in biopsies and sera from patients, respectively.

Results: IP-10 was specifically produced by SNK-6 and SNT-8. Moreover, CXCR3 was expressed on the NK cell lines. Functionally, IP-10 did not affect cell proliferation but enhanced cell invasion. In biopsy samples, IP-10 and CXCR3 expressions were detected in the lymphoma cells. Serum IP-10 levels in the patients were much higher than those of healthy controls and the levels were decreased during the complete remission phase after treatments.

Conclusions: These results suggest that IP-10 may play an important role in cell invasion in nasal NK/T-cell lymphoma through an autocrine mechanism. (Clin Cancer Res 2009;15(22):67719)

DOI： 10.1158/1078-0432.ccr-09-1052

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

researchmap

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

DOI： 10.5631/jibirin.102.433

researchmap

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

DOI： 10.5631/jibirin.102.291

researchmap

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/art.24327

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Abstract

Myeloid DNAX activation protein 12 (DAP12)-associating lectin-1 (MDL-1), also known as C-type lectin domain family 5, member A, is a type II transmembrane protein belonging to the C-type lectin family and associates with DAP12 (also called KARAP or TYROBP). It has been reported that two isoforms of MDL-1—long form (MDL-1L) and short form (MDL-1S)—exist in mice. Previously, we observed the marked induction of MDL-1 mRNA expression during the pulmonary mycobacterial infection in mice. The data suggested that the MDL-1-expressing cells were involved in immune responses against mycobacterial infection; however, little is known about the function of MDL-1 as yet. In this study, we demonstrated the significant protein expression of MDL-1L and MDL-1S in mouse neutrophils and macrophages. MDL-1L was highly glycosylated by N-linked glycan and sialic acid. Interestingly, the expression pattern of MDL-1 was different between neutrophils and macrophages. MDL-1 expression was notably induced during the differentiation of the mouse myeloid cell line 32Dcl3 into neutrophils. Additionally, we observed that MDL-1 stimulation induced a significant amount of RANTES and macrophage-derived chemokine production in 32Dcl3 cells in cooperation with signaling through TLR. MDL-1 stimulation also up-regulated CD11b expression and maintained cell survival. Our findings indicate that MDL-1, therefore, plays an important role in immune defense as a result of an innate immunity, which involves neutrophils and macrophages.

DOI： 10.1189/jlb.0508329

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

DOI： 10.5631/jibirin.101.765

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

researchmap

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Association for Cancer Research (AACR)  

Abstract

EBV-encoded latent membrane protein 1 (LMP1) has oncogenic potential and is expressed in many EBV-associated malignancies. Although LMP1 is regarded as a potential tumor-associated antigen for immunotherapy and several LMP1-specific MHC class I–restricted CTL epitopes have been reported, little is known regarding MHC class II–restricted CD4 helper T-lymphocyte (HTL) epitopes for LMP1. The goal of the present studies was to determine whether MHC class II–restricted CD4 T-cell responses could be induced against the LMP1 antigen and to evaluate the antitumor effect of these responses. We have combined the use of a predictive MHC class II binding peptide algorithm with in vitro vaccination of CD4 T cells using candidate peptides to identify naturally processed epitopes derived from LMP1 that elicit immune responses against EBV-expressing tumor cells. Peptide LMP1159-175 was effective in inducing HTL responses that were restricted by HLA-DR9, HLA-DR53, or HLA-DR15, indicating that this peptide behaves as a promiscuous T-cell epitope. Moreover, LMP1159-175–reactive HTL clones directly recognized EBV lymphoblastoid B cells, EBV-infected natural killer (NK)/T-lymphoma cells and naturally processed antigen in the form of LMP1+ tumor cell lysates presented by autologous dendritic cells. Because the newly identified epitope LMP1159-175 overlaps with an HLA-A2–restricted CTL epitope (LMP1159-167), this peptide might have the ability to induce simultaneous CTL and HTL responses against LMP1. Overall, our data should be relevant for the design and optimization of T-cell epitope–based immunotherapy against various EBV-associated malignancies, including NK/T cell lymphomas. [Cancer Res 2008;68(3):901–8]

DOI： 10.1158/0008-5472.can-07-3212

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：S. Karger AG  

Nasal natural killer (NK)/T cell lymphoma is a peculiar lymphoma with a unique immunophenotype. Etiologically, in 1990, the authors first demonstrated the presence of Epstein-Barr virus (EBV) genomes and their products in this lymphoma. EBV-specific cytotoxic T lymphocytes (CTL) are very important in controlling the long-term persistence of EBV infection. Amino acid changes encoding the CTL epi-tope on the lymphoma cells may result in a reduced CTL response. We focused on two major CTL epitopes SSCSSCPLSK (codon 340 to 349) and FLYALALLLL (codon 356 to 364) of the LMP2A gene and determined the sequence isolated from nasal NK/T cell lymphoma tissues. All isolates from 7 nasal NK/T cell lymphomas showed the same amino acid change from serine to threonine at codon 348 in the CTL epitope SSCSSCPLSK. Threonine or serine substitution at codon 348 was almost equally observed in peripheral blood EBV isolates from healthy individuals in various ethnic origins. The predominant threonine substitution of nasal NK/T cell lymphoma patients may represent disease-associated polymorphism rather than a geographic or race-associated polymorphism. The LMP2A strain including threonine substitution at codon 348 may be selected within tumors and play a role for tumor genesis in Japanese patients with nasal NK/T cell lymphoma through reduced immune recognition.

DOI： 10.1159/000106462

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Association for Cancer Research (AACR)  

Abstract

The six-transmembrane epithelial antigen of prostate (STEAP) protein is an attractive candidate for T cell–based immunotherapy because it is overexpressed in prostate cancer and various other tumor types. Several peptide epitopes capable of stimulating CTLs that killed STEAP-expressing tumor cells have been described. Our goal was the identification of helper T lymphocyte (HTL) epitopes of STEAP for the optimization of T cell–based immunotherapies against STEAP-expressing malignancies. Candidate HTL epitopes for STEAP were predicted using in silico algorithms for HLA class II–binding peptides and were tested for their ability to elicit HTL responses by in vitro peptide vaccination of CD4 T lymphocytes from healthy individuals and prostate cancer patients. Two peptides (STEAP102–116 and STEAP192–206) were effective in stimulating in vitro antitumor HTL responses in both normal individuals and prostate cancer patients. Notably, both STEAP HTL peptides behaved as promiscuous T-cell epitopes because they stimulated T cells in the context of more than one MHC class II allele. These newly described STEAP HTL epitopes could be of value for the design and optimization of T cell–based immunotherapy against STEAP-expressing tumors. [Cancer Res 2007;67(11):5498–504]

DOI： 10.1158/0008-5472.can-07-0304

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

DOI： 10.5631/jibirin.100.447

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

Quantitative real‐time polymerase chain reaction (PCR) was utilized to measure serum EBV DNA levels of BamHI W fragment and latent membrane protein 1 (LMP1) in 20 nasal natural killer (NK)/T‐cell lymphoma patients. Both serum EBV DNAs were detected at high levels in all patients, but the levels were below the limit of detection in all healthy controls. The BamHI Z fragment, Epstein–Barr‐replication activator (ZEBRA) expression was detected in a small proportion (0.1–3%) of lymphoma cells from 10 (50%) of the patients. Patients with ZEBRA expression showed significantly higher DNA levels of BamHI W and LMP1 (P = 0.0081, P = 0.004), suggesting that EBV DNA may be caused by EBV replication from lymphoma cells. Kaplan–Meier and univariate analyses revealed that high DNA levels of BamHI W and LMP1 at pre‐treatment and high BamHI W DNA level at post‐treatment were associated with short disease‐free survival and overall survival (P < 0.05, each). Although the DNA levels of BamHI W and LMP1 correlated significantly, their dynamics were not always parallel. Patients with low pre‐treatment level of both EBV DNAs showed a favorable course, in contrast to patients with high pre‐treatment level of both EBV DNAs who showed an aggressive course (P = 0.0085). More importantly, the high pre‐treatment level of both EBV DNAs was determined as the only independent prognostic factor among various prognostic factors. These data suggest that simultaneous measurement of serum levels of both BamHI W and LMP1 DNAs may be useful for diagnosis, disease monitoring, and prediction of prognosis for nasal NK/T‐cell lymphoma patients. J. Med. Virol. 79:562–572, 2007. © 2007 Wiley‐Liss, Inc.

DOI： 10.1002/jmv.20853

researchmap

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

Abstract

Allergen-specific immunotherapy using peptides is an efficient treatment for allergic diseases. Recent studies suggest that the induction of CD4+ regulatory T (Treg) cells might be associated with the suppression of allergic responses in patients after allergen-specific immunotherapy. Our aim was to identify MHC class II promiscuous T cell epitopes for the birch pollen allergen Bet v 1 capable of stimulating Treg cells with the purpose of inhibiting allergic responses. Ag-reactive CD4+ T cell clones were generated from patients with birch pollen allergy and healthy volunteers by in vitro vaccination of PBMC using Bet v 1 synthetic peptides. Several CD4+ T cell clones were induced by using 2 synthetic peptides (Bet v 1141–156 and Bet v 151–68). Peptide-reactive CD4+ T cells recognized recombinant Bet v 1 protein, indicating that these peptides are produced by the MHC class II Ag processing pathway. Peptide Bet v 1141–156 appears to be a highly MHC promiscuous epitope since T cell responses restricted by numerous MHC class II molecules (DR4, DR9, DR11, DR15, and DR53) were observed. Two of these clones functioned as typical Treg cells (expressed CD25, GITR, and Foxp3 and suppressed the proliferation and IL-2 secretion of other CD4+ T cells). Notably, the suppressive activity of these Treg cells required cell-cell contact and was not mediated through soluble IL-10 or TGF-β. The identified promiscuous MHC class II epitope capable of inducing suppressive Treg responses may have important implication for the development of peptide-based Ag-specific immunotherapy to birch pollen allergy.

DOI： 10.4049/jimmunol.178.2.1189

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s11262-006-0008-5

researchmap

Other Link： http://link.springer.com/article/10.1007/s11262-006-0008-5/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Association for Cancer Research (AACR)  

Abstract

Purpose: Adult T-cell leukemia/lymphoma induced by human T-cell leukemia virus type 1 (HTLV-1) is usually a fatal lymphoproliferative malignant disease. HTLV-1 Tax protein plays a critical role in HTLV-1-associated leukemogenesis and is an attractive target for vaccine development. Although HTLV-1 Tax is the most dominant antigen for HTLV-1-specific CD8+ CTLs in HTLV-1-infected individuals, few epitopes recognized by CD4+ helper T lymphocytes in HTLV-1 Tax protein have been described. The aim of the present study was to study T-helper-cell responses to HTLV-1 Tax and to identify naturally processed MHC class II–restricted epitopes that could be used for vaccine development.

Experimental Design: An MHC class II binding peptide algorithm was used to predict potential T-helper cell epitope peptides from HTLV-1 Tax. We assessed the ability of the corresponding peptides to elicit helper T-cell responses by in vitro vaccination of purified CD4+ T lymphocytes.

Results: Peptides Tax191-205 and Tax305-319 were effective in inducing T-helper-cell responses. Although Tax191-205 was restricted by the HLA-DR1 and DR9 alleles, responses to Tax305-319 were restricted by either DR15 or DQ9. Both these epitopes were found to be naturally processed by HTLV-1+ T-cell lymphoma cells and by autologous antigen-presenting cells that were pulsed with HTLV-1 Tax+ tumor lysates. Notably, the two newly identified helper T-cell epitopes are found to lie proximal to known CTL epitopes, which will facilitate the development of prophylactic peptide–based vaccine capable of inducing simultaneous CTL and T-helper responses.

Conclusion: Our data suggest that HTLV-1 Tax protein could serve as tumor-associated antigen for CD4+ helper T cells and that the present epitopes might be used for T-cell-based immunotherapy against tumors expressing HTLV-1.

DOI： 10.1158/1078-0432.ccr-06-0384

researchmap

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Association for Cancer Research (AACR)  

Abstract

Purpose: Nasal natural killer (NK)/T-cell lymphoma is associated with EBV and has distinct clinical and histologic features. However, little is known about its genetic features. In this study, we examined the genes expressed by SNK-6 and SNT-8 cells, which were established from nasal NK/T-cell lymphomas, and found that interleukin (IL)-9 was specifically expressed in these two cell lines.

Experimental Design: cDNA array was used to examine the genes expressed by SNK-6 and SNT-8 cells. Expression of IL-9 and IL-9 receptor was investigated by reverse transcription-PCR, ELISA, and flow cytometry. Cell growth was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Immunohistologic staining and ELISA were used to examine IL-9 expression in biopsies and sera from patients, respectively.

Results: In cDNA array, expression of IL-9 mRNA was much higher in SNK-6 and SNT-8 cells than in NK-92 cells from non-nasal NK-cell lymphoma and peripheral blood mononuclear cells from healthy volunteers. Furthermore, IL-9 was specifically expressed by SNK-6 and SNT-8 cells but not by other NK-cell, NK-like T-cell, and T-cell lymphoma/leukemia cell lines. IL-9 receptor was also expressed on the surfaces of SNK-6 and SNT-8 cells. An IL-9-neutralizing antibody inhibited the growth of these two cell lines, whereas recombinant human IL-9 enhanced their growth. Most significantly, IL-9 was present in biopsies and sera from patients with this lymphoma.

Conclusions: These results suggest that IL-9 plays an important role in nasal NK/T-cell lymphoma possibly via an autocrine mechanism.

DOI： 10.1158/1078-0432.ccr-05-1426

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s00262-005-0071-0

researchmap

Other Link： http://link.springer.com/article/10.1007/s00262-005-0071-0/fulltext.html

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

DOI： 10.5631/jibirin.98.577

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Association for Cancer Research (AACR)  

Abstract

Purpose: T cell–based immunotherapy via the in vitro or in vivo expansion of prostate tumor-associated antigen (TAA)–specific T lymphocytes is one of the most promising therapeutic approaches to treat prostate cancer. T-cell alternate reading frame protein (TARP) is a mitochondrial protein that is specifically expressed in prostate epithelial cells. We have done experiments aimed at identifying helper T lymphocyte (HTL) epitopes for TARP for the design of T cell–based immunotherapy for prostate cancer.

Experimental Design: Dendritic cells from normal donors were pulsed with synthetic peptides derived from TARP, which were predicted to serve as HTL epitopes. These dendritic cells were used to stimulate CD4+ T cells in vitro to trigger HTL responses against TARP. T-cell responses to these peptides were also studied with lymphocytes from prostate cancer patients.

Results: The two peptides, TARP1-14 and TARP14-27, were shown to elicit effective in vitro HTL responses using lymphocytes from both normal volunteers and prostate cancer patients. Peptide TARP1-14-reactive HTLs were found restricted by HLA-DR53 and could recognize naturally processed protein antigen derived from tumor cells, which was presented by autologous dendritic cells. Most significantly, stimulation with peptide TARP14-27 generated four HTL lines restricted by HLA-DR1, HLA-DR9, HLA-DR13, and HLA-DR15, some of which capable of recognizing naturally processed antigens presented by dendritic cell or directly by TARP-positive tumor cells.

Conclusions: Our results show that TARP constitutes a TAA that can be recognized by tumor-reactive HTL. The newly described TARP epitopes could be used to optimize and improve T-cell epitope–based immunotherapy against prostate and other tumors expressing TARP.

DOI： 10.1158/1078-0432.ccr-04-2238

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Allergology  

We investigated the positive rate of specific IgE to various allergens in 548 patients with allergic rhinitis who visited 13 hospitals in Hokkaido in 2001. House dust and mite were most common allergen in our study. On the other hand, the positive rate for pollens were in the order of birch, timothy, orchard grass, and mugwort. In comparison with past study, the positive rate to birch had increased and the positive rate to timothy and orchard grass had decreased. The positive rate of specific IgE to birch was higher in Asahikawa, its neighborhood, and Sapporo, while Kushiro, Tomakomai, Wakkanai, and Nemuro lie on the coast were lower region. These findings suggested that the positive rate of specific IgE to birch varies in different region even in the same island, Hokkaido and might be influenced by climate.

DOI： 10.15036/arerugi.54.59

CiNii Books

researchmap

Other Link： http://search.jamas.or.jp/link/ui/2005098062

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Association for Cancer Research (AACR)  

Abstract

Purpose: Human T-cell leukemia virus type I (HTLV-I) can cause an adult T-cell leukemia/lymphoma (ATLL). Because ATLL is a life-threatening lymphoproliferative disorder and is resistant to chemotherapy, the establishment and enhancement of T-cell immunity to HTLV-I through the development of therapeutic vaccines could be of value. Thus, the identification of HTLV-I epitopes for both CD8+ and CD4+ T cells should facilitate the development of effective vaccines. Although numerous HTLV-I epitopes for CTLs have been identified, few epitopes recognized by CD4+ helper T cells against this virus have been described.

Experimental Design: Synthetic peptides prepared from several regions of the HTLV-I envelope (Env) sequence that were predicted to serve as helper T-cell epitopes were prepared with use of computer-based algorithms and tested for their capacity to trigger in vitro helper T-cell responses using lymphocytes from normal volunteers.

Results: The results show that the HTLV-I–Env317–331, and HTLV-I–Env384–398-reactive helper T lymphocytes restricted by HLA-DQw6 and HLA-DR15, respectively, could recognize intact HTLV-I+ T-cell lymphoma cells and, as a consequence, secrete lymphokines. In addition, HTLV-I Env196–210-reactive helper T lymphocytes restricted by HLA-DR9 were able to directly kill HTLV-I+ lymphoma cells and recognize naturally processed antigen derived from killed HTLV-I+ lymphoma cells, which was presented to the helper T cells by autologous antigen-presenting cells.

Conclusions: The present findings hold relevance for the design and optimization of T-cell epitope-based immunotherapy against HTLV-I–induced diseases such as ATLL.

DOI： 10.1158/1078-0432.ccr-04-0897

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

DOI： 10.5631/jibirin.97.499

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1074/jbc.m312766200

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

DOI： 10.5631/jibirin.97.113

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

DOI： 10.5631/jibirin.96.51

researchmap

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：The Society of Practical Otolaryngology  

DOI： 10.5631/jibirin.95.1053

researchmap

Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY  

Web of Science

researchmap

Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.1080/21645515.2017.1395995

researchmap

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：Japan Association of Endocrine Surgeons･Japanese Society of Thyroid Surgery  

DOI： 10.11226/jaesjsts.33.4_215

CiNii Books

researchmap

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：Japan Society of Immunology and Allergology in Otolaryngology  

DOI： 10.5648/jjiao.32.185

researchmap

Authorship：Lead author   Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.4161/onci.28440

researchmap

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：医学書院  

DOI： 10.11477/mf.1411102187

researchmap

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：Japan Society of Immunology and Allergology in Otolaryngology  

DOI： 10.5648/jjiao.29.209

researchmap

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：医学書院  

DOI： 10.11477/mf.1411101911

researchmap

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：東京医学社  

researchmap

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：丹水社  

researchmap

Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s10147-009-0882-7

researchmap

Other Link： http://link.springer.com/article/10.1007/s10147-009-0882-7/fulltext.html

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：耳鼻咽喉科展望会  

researchmap

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

researchmap