2025/08/22 更新

写真a

ムラタ ケンジ
村田 憲治
所属
附属免疫学研究所 分子医学部門 助教
職名
助教
ORCID ID
0000-0002-2613-5144
外部リンク

研究キーワード

  • 骨軟部肉腫

  • T細胞受容体

  • 腫瘍免疫学

  • 養子免疫療法

研究分野

  • ライフサイエンス / 分子生物学

  • ライフサイエンス / 免疫学

  • ライフサイエンス / 整形外科学

経歴

  • 札幌医科大学   医学部附属研究所免疫学研究所分子医学部門/医学部病理学講座病理第一分野   助教

    2025年4月 - 現在

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    国名:日本国

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  • 札幌医科大学   医学部附属研究所免疫学研究所分子医学部門/医学部病理学第一講座   特任助教

    2023年11月 - 2025年3月

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    国名:日本国

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  • 札幌医科大学   医学部附属フロンティア医学研究所病態情報学/医学部病理学第一講座   特任助教

    2022年6月 - 2023年10月

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  • 札幌医科大学   医学部 病理学第一講座   特任助教

    2020年4月 - 2022年5月

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  • プリンセスマーガレットがんセンター   平野研究室   博士研究員

    2016年4月 - 2020年3月

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論文

  • Landscape mapping of shared antigenic epitopes and their cognate TCRs of tumor-infiltrating T lymphocytes in melanoma. 国際誌

    Kenji Murata, Munehide Nakatsugawa, Muhammed A Rahman, Linh T Nguyen, Douglas G Millar, David T Mulder, Kenji Sugata, Hiroshi Saijo, Yukiko Matsunaga, Yuki Kagoya, Tingxi Guo, Mark Anczurowski, Chung-Hsi Wang, Brian D Burt, Dalam Ly, Kayoko Saso, Alexandra Easson, David P Goldstein, Michael Reedijk, Danny Ghazarian, Trevor J Pugh, Marcus O Butler, Tak W Mak, Pamela S Ohashi, Naoto Hirano

    eLife   9   2020年4月

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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)  

    HLA-restricted T cell responses can induce antitumor effects in cancer patients. Previous human T cell research has largely focused on the few HLA alleles prevalent in a subset of ethnic groups. Here, using a panel of newly developed peptide-exchangeable peptide/HLA multimers and artificial antigen-presenting cells for 25 different class I alleles and greater than 800 peptides, we systematically and comprehensively mapped shared antigenic epitopes recognized by tumor-infiltrating T lymphocytes (TILs) from eight melanoma patients for all their class I alleles. We were able to determine the specificity, on average, of 12.2% of the TILs recognizing a mean of 3.1 shared antigen-derived epitopes across HLA-A, B, and C. Furthermore, we isolated a number of cognate T cell receptor genes with tumor reactivity. Our novel strategy allows for a more complete examination of the immune response and development of novel cancer immunotherapy not limited by HLA allele prevalence or tumor mutation burden.

    DOI: 10.7554/eLife.53244

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  • The size of CD8+ infiltrating T cells is a prognostic marker for esophageal squamous cell carcinoma

    Kengo Shigehara, Noriko Kawai, Tomohide Shirosaki, Yuma Ebihara, Aiko Murai, Akari Takaya, Serina Tokita, Kenta Sasaki, Naoki Shijubou, Terufumi Kubo, Kenji Murata, Takayuki Kanaseki, Tomohide Tsukahara, Yutaka Hatanaka, Tomoko Mitsuhashi, Toshiaki Shichinohe, Yoshihiko Hirohashi, Satoshi Hirano, Toshihiko Torigoe

    Scientific Reports   15 ( 1 )   2025年7月

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

    その他リンク: https://www.nature.com/articles/s41598-025-10885-3

    DOI: 10.1038/s41598-025-10885-3

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  • SMU-pRMS: a novel cell line of pleomorphic rhabdomyosarcoma

    Naoya Nakahashi, Makoto Emori, Yasutaka Murahashi, Kazuyuki Murase, Junya Shimizu, Kenji Murata, Tomohide Tsukahara, Shintaro Sugita, Kousuke Iba, Kohichi Takada, Makoto Osanai, Atsushi Teramoto

    Human Cell   38 ( 5 )   2025年7月

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

    その他リンク: https://link.springer.com/article/10.1007/s13577-025-01263-2/fulltext.html

    DOI: 10.1007/s13577-025-01263-2

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  • An SNP-dependent cancer-testis antigenic epitope serves as a promising immunotherapeutic target for cancer

    Kenji Murata, Tomoyuki Minowa, Tomohide Tsukahara, Taku Yoshida, Akiko Minami, Munehide Nakatsugawa, Yuka Mizue, Aiko Murai, Serina Tokita, Kenta Sasaki, Hisashi Uhara, Terufumi Kubo, Takayuki Kanaseki, Toshihiko Torigoe, Yoshihiko Hirohashi

    OncoImmunology   14 ( 1 )   2025年7月

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    担当区分:筆頭著者, 責任著者   掲載種別:研究論文(学術雑誌)   出版者・発行元:Informa UK Limited  

    DOI: 10.1080/2162402x.2025.2528110

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  • Large number of CD68+/CD163+ Hofbauer cells and characteristic vascular structural alterations in the placental villi of cases with placenta accreta spectrum.

    Hazuki Kashiwagi, Kengo Shigehara, Terufumi Kubo, Yoshihiko Hirohashi, Tasuku Mariya, Kazuhiko Matsuo, Tomoyuki Minowa, Shin-Ichi Ishioka, Kenji Murata, Takayuki Kanaseki, Tomohide Tsukahara, Tadashi Hasegawa, Tsuyoshi Saito, Toshihiko Torigoe

    Medical molecular morphology   2025年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Placenta accreta spectrum (PAS) is a serious disease leading to complications and maternal death. The objective of the study was to characterize the placental villi and blood vessels of PAS villi histopathologically. We investigated 10 cases of PAS (five cases of placenta increta, two cases of placenta accreta, and three cases of placenta percreta) histologically. Immunohistochemical staining using anti-CD68 or anti-CD163 antibodies was performed to detect and count Hofbauer cells. Immunohistochemical staining with an anti-CD34 antibody was used to detect vascular endothelial cells, and the number and area of vessels were analyzed. The numbers of CD68-positive or CD163-positive Hofbauer cells were larger in PAS cases compared with control cases. The vascular area in villi was smaller in PAS cases compared with control cases. The number of blood vessels in villi was slightly higher in PAS cases than in control cases. The numbers of Hofbauer cells and vessels in villi were larger in PAS cases compared with control cases, whereas the area of vessels in villi was smaller in PAS cases compared with control cases. Although their biological meaning is elusive, these findings provide novel insights into the pathogenesis of PAS, particularly regarding the role of Hofbauer cells in immune-suppressive role and angiogenesis and the alterations in vascular structure and hemodynamics in the chorionic villi.

    DOI: 10.1007/s00795-025-00432-4

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  • Development of a T cell engaging bispecific antibody targeting long non-coding RNA PVT1

    Hirotaka Kato, Tomohide Tsukahara, Kenji Murata, Hiromu Nishikata, Yuka Mizue, Takashi Sasaya, Terufumi Kubo, Takayuki Kanaseki, Yoshihiko Hirohashi, Atsushi Oyagi, Tatsuo Maeda, Akihiro Miyazaki, Toshihiko Torigoe

    Cancer Immunology, Immunotherapy   74 ( 4 )   2025年3月

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

    その他リンク: https://link.springer.com/article/10.1007/s00262-025-03976-7/fulltext.html

    DOI: 10.1007/s00262-025-03976-7

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  • MHC class I trafficking signal improves induction of cytotoxic T lymphocyte using artificial antigen presenting cells

    Kenta Sasaki, Kenji Murata, Tomoyuki Minowa, Naoki Shijubou, Hiroki Kobayashi, Munehide Nakatsugawa, Aiko Murai, Yuka Mizue, Terufumi Kubo, Takayuki Kanaseki, Tomohide Tsukahara, Hisashi Uhara, Akemi Ishida-Yamamoto, Yoshihiko Hirohashi, Toshihiko Torigoe

    Biochemistry and Biophysics Reports   41   101946 - 101946   2025年3月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.bbrep.2025.101946

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  • Characteristic TARC/CCL17 expression in the salivary gland of IgG4-related disease: potential diagnostic utility and insights into pathogenesis. 国際誌

    Nanako Kikuchi, Sae Hatanaka, Terufumi Kubo, Ryuta Kamekura, Masatoshi Kanda, Takuya Kakuki, Takashi Sasaya, Kengo Mita, Hiroki Kobayashi, Hajime Ikai, Kenta Sasaki, Naoki Shijubou, Kenji Murata, Takayuki Kanaseki, Tomohide Tsukahara, Yoshihiko Hirohashi, Tadashi Hasegawa, Akihiro Miyazaki, Hiroki Takahashi, Ken-Ichi Takano, Toshihiko Torigoe

    Immunological medicine   1 - 7   2025年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Immunoglobulin G4-related disease (IgG4-RD) is a chronic inflammatory condition of unknown etiology characterized by lymphocytic infiltration, fibrosis, and infiltration of IgG4-positive plasma cells. It affects various organs, including the pancreas and salivary glands. Immunological abnormalities are suspected to play a role in its pathogenesis, and there is an epidemiological link to allergic conditions and type 2 inflammation. This study focused on the expression of thymus and activation-regulated chemokine (TARC)/CCL17, which is involved in the migration of T helper 2 and/or regulatory T cells, in salivary gland tissues of patients with IgG4-RD. We analyzed 60 salivary gland biopsy samples obtained from patients at Sapporo Medical University Hospital between 2015 and 2020. Immunohistochemical analysis revealed TARC/CCL17 positivity in 87.2% of histologically confirmed IgG4-RD cases and negativity in 84.6% of histologically unconfirmed but clinically suspected IgG4-RD cases. There was a significant correlation between histologically confirmed IgG4-RD and TARC/CCL17 expression, suggesting its potential diagnostic utility and possible involvement in the pathogenesis of IgG4-RD.

    DOI: 10.1080/25785826.2025.2460910

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  • Establishment of potent TCR-T cells specific for cisplatin-resistance related tumor-associated antigen, CLSPN using codon-optimization. 国際誌

    Kanta Hori, Shuhei Yamada, Kenji Murata, Haruka Miyata, Yuka Mizue, Aiko Murai, Tomoyuki Minowa, Kenta Sasaki, Naoki Shijubou, Terufumi Kubo, Rena Morita, Serina Tokita, Takayuki Kanaseki, Tomohide Tsukahara, Takashige Abe, Nobuo Shinohara, Yoshihiko Hirohashi, Toshihiko Torigoe

    Human vaccines & immunotherapeutics   20 ( 1 )   2414542 - 2414542   2024年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Adoptive T cell therapy, using T cell receptor-engineered T (TCR-T) cells and chimeric antigen receptor T (CAR-T) cells, is a potent immunotherapy option. Bladder cancer is a prevalent urological malignancy, particularly in cases of muscle invasion and metastasis, for which systemic therapy is crucial. Immunotherapy utilizing immune checkpoint blockade has been approved for bladder cancer treatment. The antitumor effect of an immune checkpoint blockade based on cytotoxic T cells (CTLs) and the patient's immune status is essential. The chemotherapeutic drug cisplatin (CDDP) is a key drug in bladder cancer treatment. However, it has been shown to suppress T cells, making combination therapy with CDDP and immunotherapy difficult. To address this, we developed TCR-T cells specific for bladder cancer cells. In previous studies, we found that the tumor-associated antigen CLSPN is overexpressed in CDDP-resistant bladder cancer cells and that the antigenic peptide HLA-A*02:01/CLSPN1254-1262, encoded by CLSPN, could be targeted by a CTL clone. The TCR was cloned from the HLA-A*02:01/CLSPN1254-1262 specific CTL clone yc3. We also designed a codon-optimized TCR sequence using GeneArt® GeneOptimizer® (Opt TCR) and compared the TCR-T cells using the original TCR sequence (Ori TCR-T cells) and the codon-optimized TCR sequence (Opt TCR-T cells). Opt TCR-T cells exhibited higher TCR transduction efficiency, higher TCR expression levels, higher avidity, and greater cytotoxicity than did Ori TCR-T cells. These results suggest that HLA-A*02:01/CLSPN1254-1262 specific Opt TCR-T cells are promising candidates for CDDP combination therapy.

    DOI: 10.1080/21645515.2024.2414542

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  • Identification and phenotypic characterization of neoantigen-specific cytotoxic CD4+ T cells in endometrial cancer

    Minami Fusagawa, Serina Tokita, Kenji Murata, Tasuku Mariya, Mina Umemoto, Shintaro Sugita, Kazuhiko Matsuo, Yoshihiko Hirohashi, Tsuyoshi Saito, Takayuki Kanaseki, Toshihiko Torigoe

    Cancer Immunology Research   2024年12月

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    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

    Tumor-reactive CD4+ T cells often accumulate in the tumor microenvironment (TME) in human cancer, but their functions and roles in antitumor responses remain elusive. Here, we investigated the immunopeptidome of HLA class II–positive (HLA-II+) endometrial cancer with an inflamed TME using a proteogenomic approach. We identified HLA-II neoantigens, one of which induced polyclonal CD4+ tumor-infiltrating lymphocyte (TIL) responses. We then experimentally demonstrated that neoantigen-specific CD4+ TILs lyse target cells in an HLA-II–dependent manner. Single cell transcriptomic analysis of the TME coupled with T-cell receptor (TCR) sequencing revealed the presence of CD4+ T-cell clusters characterized by CXCL13 expression. The CXCL13+ clusters contained two subclusters with distinct cytotoxic gene expression patterns. The identified neoantigen-specific CD4+ T cells were found exclusively in one of the CXCL13+ subclusters characterized by granzyme B and CCL5 expression. These results demonstrate the involvement of tumor-reactive CD4+ T cells with cytotoxic function in immune surveillance of endometrial cancer and reveal their transcriptomic signature.

    DOI: 10.1158/2326-6066.cir-24-0514

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  • Single-cell profiling of acral melanoma infiltrating lymphocytes reveals a suppressive tumor microenvironment. 国際誌

    Tomoyuki Minowa, Kenji Murata, Yuka Mizue, Aiko Murai, Munehide Nakatsugawa, Kenta Sasaki, Serina Tokita, Terufumi Kubo, Takayuki Kanaseki, Tomohide Tsukahara, Toshiya Handa, Sayuri Sato, Kohei Horimoto, Junji Kato, Tokimasa Hida, Yoshihiko Hirohashi, Hisashi Uhara, Toshihiko Torigoe

    Science translational medicine   16 ( 776 )   eadk8832   2024年12月

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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)  

    Acral lentiginous melanoma (ALM) is the most common melanoma subtype in non-Caucasians. Despite advances in cancer immunotherapy, current immune checkpoint inhibitors remain unsatisfactory for ALM. Hence, we conducted comprehensive immune profiling using single-cell phenotyping with reactivity screening of the T cell receptors of tumor-infiltrating T lymphocytes (TILs) in ALM. Compared with cutaneous melanoma, ALM showed a lower frequency of tumor-reactive CD8 clusters and an enrichment of regulatory T cells with direct tumor recognition ability, suggesting a suppressive immune microenvironment in ALM. Tumor-reactive CD8 TILs showed heterogeneous expression of coinhibitory molecules, including KLRC1 (NKG2A), in subpopulations with therapeutic implications. Overall, our study provides a foundation for enhancing the efficacy of immunotherapy in ALM.

    DOI: 10.1126/scitranslmed.adk8832

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  • Assessment of cancer cell-expressed HLA class I molecules and their immunopathological implications. 国際誌

    Terufumi Kubo, Shiori Asano, Kenta Sasaki, Kenji Murata, Takayuki Kanaseki, Tomohide Tsukahara, Yoshihiko Hirohashi, Toshihiko Torigoe

    HLA   103 ( 5 )   e15472   2024年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Immunotherapy using immune checkpoint inhibitors (ICIs) has shown superior efficacy compared with conventional chemotherapy in certain cancer types, establishing immunotherapy as the fourth standard treatment alongside surgical intervention, chemotherapy, and radiotherapy. In cancer immunotherapy employing ICIs, CD8-positive cytotoxic T lymphocytes are recognized as the primary effector cells. For effective clinical outcomes, it is essential that the targeted cancer cells express HLA class I molecules to present antigenic peptides derived from the tumor. However, cancer cells utilize various mechanisms to downregulate or lose HLA class I molecules from their surface, resulting in evasion from immune surveillance. Correlations between prognosis and the integrity of HLA class I molecules expressed by cancer cells have been consistently found across different types of cancer. This paper provides an overview of the regulatory mechanisms of HLA class I molecules and their role in cancer immunotherapy, with a particular emphasis on the significance of utilizing pathological tissues to evaluate HLA class I molecules expressed in cancer cells.

    DOI: 10.1111/tan.15472

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  • Aldehyde Dehydrogenese-1 High Cancer Stem-like Cells/Cancer-initiating Cells Escape from Cytotoxic T Lymphocytes due to Lower Expression of Human Leukocyte Antigen Class 1. 国際誌

    Tomohide Shirosaki, Noriko Kawai, Yuma Ebihara, Aiko Murai, Terufumi Kubo, Rena Morita, Kenji Murata, Takayuki Kanaseki, Tomohide Tsukahara, Toshiaki Shichinohe, Yoshihiko Hirohashi, Satoshi Hirano, Toshihiko Torigoe

    Anticancer research   44 ( 5 )   1877 - 1883   2024年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND/AIM: Human gastric cancer stem-like cells (CSCs)/cancer-initiating cells can be identified as aldehyde dehydrogenase-high (ALDHhigh) cells. Cancer immunotherapy employing immune checkpoint blockade has been approved for advanced gastric cancer cases. However, the effectiveness of cancer immunotherapy against gastric CSCs/CICs remains unclear. This study aimed to investigate the susceptibility of gastric CSCs/CICs to immunotherapy. MATERIALS AND METHODS: Gastric CSCs/CICs were isolated as ALDHhigh cells using the human gastric cancer cell line, MKN-45. ALDHhigh clone cells and ALDHlow clone cells were isolated using the ALDEFLUOR assay. ALDH1A1 expression was assessed via qRT-PCR. Sphere-forming ability was evaluated to confirm the presence of CSCs/CICs. A model neoantigen, AP2S1, was over-expressed in ALDHhigh clone cells and ALDHlow clone cells, and susceptibility to AP2S1-specific TCR-T cells was assessed using IFNγ ELISPOT assay. RESULTS: Three ALDHhigh clone cells were isolated from MKN-45 cells. ALDHhigh clone cells exhibited a stable phenotype in in vitro culture for more than 2 months. The High-36 clone cells demonstrated the highest sphere-forming ability, whereas the Low-8 cells showed the lowest sphere-forming ability. High-36 cells exhibited lower expression of HLA-A24 compared to Low-8 cells. TCR-T cells specific for AP2S1 showed lower reactivity to High-36 cells compared to Low-8 cells. CONCLUSION: High-36 cells and Low-8 cells represent novel gastric CSCs/CICs and non-CSCs/CICs, respectively. ALDHhigh CSCs/CICs evade T cells due to lower expression of HLA class 1.

    DOI: 10.21873/anticanres.16989

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  • CD8-positive T Cell Infiltration With Human Leukocyte Antigen Class 1 Expression Predicts Patients With Stage IV Colorectal Cancer Survival. 国際誌

    Tetsuta Satoyoshi, Yoshihiko Hirohashi, Koichi Okuya, Masaaki Miyo, Emi Akizuki, Masayuki Ishii, Ryo Miura, Terufumi Kubo, Kenji Murata, Takayuki Kanaseki, Tomohide Tsukahara, Ichiro Takemasa, Toshihiko Torigoe

    Anticancer research   44 ( 4 )   1603 - 1610   2024年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND/AIM: The immune microenvironment in cancer correlates with cancer progression and patient prognosis. Cancer immune microenvironment evaluation, based on CD3+ and CD8+ T cell infiltration at the center and invasive margin of the tumor, is defined as the immunoscore. An international multicenter analysis revealed that the immunoscore can accurately predict the prognosis of patients with colorectal cancer (CRC) (stage I, II, and III). However, no markers are currently available to predict the prognosis in patients with stage IV CRC. We thus aimed to analyze the immune microenvironment in patients with stage IV CRC in this study. PATIENTS AND METHODS: We analyzed the immune microenvironment of patients with stage IV CRC using immunohistochemical (IHC) staining. We evaluated the expressions of CD8 and the cases were divided into CD8 high (CD8Hi) and CD8 low (CD8Low) groups according to median CD8 expression. HLA class 1 (HLA1) expression was also evaluated using IHC staining and the cases were divided into HLA1Hi group and HLA1Low group according to 50% of HLA1 expression rate. CD8×HLA1 score was defined by the combination of CD8 and HLA1 expressions. RESULTS: CD8Hi and HLA1Hi cases were associated with better prognosis compared with CD8Low and HLA1Low cases according to a log-rank test, respectively. We defined a novel biomarker by combining CD8+ T-cell infiltration and HLA1 expression, referred to as the CD8×HLA1 score. We found that CD8×HLA1Hi cases predicted patient prognosis better than CD8×HLA1Int and CD8×HLA1Low according to a log-rank test. CONCLUSION: The combination of CD8+ T cell infiltration and HLA1 expression is crucial for cancer immune microenvironment evaluation in CRCs.

    DOI: 10.21873/anticanres.16958

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  • Distinct induction pathways of heat shock protein 27 in human keratinocytes: Heat stimulation or capsaicin through phosphorylation of heat shock factor 1 at serine 326 and/or suppression of ΔNp63. 国際誌

    Terufumi Kubo, Kenta Sasaki, Sayuri Sato, Tomoyuki Minowa, Tokimasa Hida, Kenji Murata, Takayuki Kanaseki, Tomohide Tsukahara, Yoshihiko Hirohashi, Hisashi Uhara, Toshihiko Torigoe

    Biochemical and biophysical research communications   708   149817 - 149817   2024年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Epidermal keratinocytes, forming the outermost layer of the human body, serve as a crucial barrier against diverse external stressors such as ultraviolet radiation. Proper keratinocyte differentiation and effective responses to external stimuli are pivotal for maintaining barrier integrity. Heat is one such stimulus that triggers the synthesis of heat shock proteins (HSPs) when cells are exposed to temperatures above 42 °C. Additionally, activation of the transient receptor potential cation channel subfamily V member 1 (TRPV1) occurs at 42 °C. Here, we explore the interplay between TRPV1 signaling and HSP induction in human keratinocytes. Both heat and capsaicin, a TRPV1 agonist, induce expression of HSP27, HSP70, and HSP90 in keratinocytes. Interestingly, pharmacological inhibition of TRPV1 attenuates heat-induced HSP27 expression, but not that of HSP70 or HSP90. Furthermore, both heat and capsaicin stimulation result in distinct phosphorylation patterns of heat shock factor 1 (HSF1), with phosphorylation at serine 326 being a common feature. Notably, genetic manipulation to mimic dephosphorylation of HSF1 at serine 326 reduces HSP27 levels. Additionally, ΔNp63, a key regulator of epidermal differentiation, negatively modulates HSP27 expression independently of HSF1 phosphorylation status. While heat stimulation has no effect on ΔNp63 expression, capsaicin reduces its levels. The precise role of TRPV1 signaling in keratinocytes warrants further investigation for a comprehensive understanding of its impact on barrier function.

    DOI: 10.1016/j.bbrc.2024.149817

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  • Prognostic significance of immunohistochemical classification utilizing biopsy specimens in patients with extensive-disease small-cell lung cancer treated with first-line chemotherapy and immune checkpoint inhibitors. 国際誌

    Naoki Shijubou, Toshiyuki Sumi, Terufumi Kubo, Kenta Sasaki, Tomohide Tsukahara, Takayuki Kanaseki, Kenji Murata, Yoshiko Keira, Kotomi Terai, Tatsuru Ikeda, Yuichi Yamada, Hirofumi Chiba, Yoshihiko Hirohashi, Toshihiko Torigoe

    Journal of cancer research and clinical oncology   150 ( 3 )   125 - 125   2024年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PURPOSE: Although immune checkpoint inhibitors (ICIs), together with cytotoxic chemotherapy (chemoimmunotherapy), have been adapted for the initial treatment of extensive-disease small-cell lung cancer (ED-SCLC), they have achieved limited success. In ED-SCLC, a subtype of SCLC, the expression of immune-related molecules and clinical data are not well understood in relation to ICI treatment efficiency. METHODS: We examined lung biopsy specimens from patients diagnosed with ED-SCLC treated with chemoimmunotherapy or chemotherapy. SCLC subtype, expression of HLA class I, and infiltration of CD8-positive cells were examined using immunohistochemistry (IHC). Subsequently, the association between clinical factors, IHC results, and progression-free survival or overall survival was assessed. RESULTS: Most of the cases showed the achaete-scute homolog 1 (ASCL1) subtype. Among the 75 SCLC cases, 29 expressed high levels of HLA class I, while 46 showed low levels or a negative result; 33 patients were characterized as CD8-high, whereas 42 were CD8-low. In the chemoimmunotherapy cohort, multivariate analysis revealed a correlation between CD8-high and improved survival. Specifically, patients in the CD8-high group of the chemoimmunotherapy cohort experienced enhanced survival compared to those in the chemotherapy cohort, which was attributed to ICI addition. IHC subtype analysis demonstrated a survival advantage in the SCLC-I and SCLC-A groups when ICI was combined with chemotherapy compared to chemotherapy alone. CONCLUSION: Our study highlights the predictive value of IHC-classified subtypes and CD8-positive cell infiltration in estimating outcomes for patients with ED-SCLC treated with chemoimmunotherapy as a first-line therapy. These findings have practical implications for daily clinical assessments and treatment decisions.

    DOI: 10.1007/s00432-024-05652-2

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  • NF9 peptide specific cytotoxic T lymphocyte clone cross react to Y453F mutation of SARS-CoV-2 virus spike protein. 国際誌

    Aiko Murai, Terufumi Kubo, Takayuki Ohkuri, Junko Yanagawa, Yuki Yajima, Akemi Kosaka, Dongliang Li, Toshihiro Nagato, Kenji Murata, Takayuki Kanaseki, Tomohide Tsukahara, Takeshi Nagasaki, Yoshihiko Hirohashi, Hiroya Kobayashi, Toshihiko Torigoe

    Immunological medicine   1 - 7   2024年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The recognition by cytotoxic T cells (CTLs) is essential for the clearance of SARS-CoV-2 virus-infected cells. Several viral proteins have been described to be recognized by CTLs. Among them, the spike (S) protein is one of the immunogenic proteins. The S protein acts as a ligand for its receptors, and several mutants with different affinities for its cognate receptors have been reported, and certain mutations in the S protein, such as L452R and Y453F, have been found to inhibit the HLA-A24-restricted CTL response. In this study, we conducted a screening of candidate peptides derived from the S protein, specifically targeting those carrying the HLA-A24 binding motif. Among these peptides, we discovered that NF9 (NYNYLYRLF) represents an immunogenic epitope. CTL clones specific to the NF9 peptide were successfully established. These CTL clones exhibited the ability to recognize endogenously expressed NF9 peptide. Interestingly, the CTL clone demonstrated cross-reactivity with the Y453F peptide (NYNYLFRLF) but not with the L452R peptide (NYNYRYRLF). The CTL clone was able to identify the endogenously expressed Y453F mutant peptide. These findings imply that the NF9-specific CTL clone possesses the capability to recognize and respond to the Y453F mutant peptide.

    DOI: 10.1080/25785826.2024.2304363

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  • Development of T cell receptor-engineered T cells targeting the sarcoma-associated antigen papillomavirus binding factor. 国際誌

    Shuto Hamada, Tomohide Tsukahara, Yuto Watanabe, Kenji Murata, Yuka Mizue, Terufumi Kubo, Takayuki Kanaseki, Yoshihiko Hirohashi, Makoto Emori, Munehide Nakatsugawa, Atsushi Teramoto, Toshihiko Yamashita, Toshihiko Torigoe

    Cancer science   115 ( 1 )   24 - 35   2024年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We previously identified papillomavirus binding factor (PBF) as an osteosarcoma antigen recognized by an autologous cytotoxic T lymphocyte clone. Vaccination with PBF-derived peptide presented by HLA-A24 (PBF peptide) elicited strong immune responses. In the present study, we generated T cell receptor-engineered T cells (TCR-T cells) directed against the PBF peptide (PBF TCR-T cells). PBF TCR was successfully transduced into T cells and detected using HLA-A*24:02/PBF peptide tetramer. PBF TCR-T cells generated from a healthy donor were highly expanded and recognized T2-A24 cells pulsed with PBF peptide, HLA-A24+ 293T cells transfected with PBF cDNA, and sarcoma cell lines. To establish an adoptive cell therapy model, we modified the PBF TCR by replacing both α and β constant regions with those of mice (hybrid PBF TCR). Hybrid PBF TCR-T cells also showed reactivity against T2-A24 cells pulsed with PBF peptide and to HLA-A24+ 293T cells transfected with various lengths of PBF cDNA including the PBF peptide sequence. Subsequently, we generated target cell lines highly expressing PBF (MFH03-PBF [short] epitope [+]) containing PBF peptide with in vivo tumorigenicity. Hybrid PBF TCR-T cells exhibited antitumor effects compared with mock T cells in NSG mice xenografted with MFH03-PBF (short) epitope (+) cells. CD45+ T cells significantly infiltrated xenografted tumors only in the hybrid PBF TCR T cell group and most of these cells were CD8-positive. CD8+ T cells also showed Ki-67 expression and surrounded the CD8-negative tumor cells expressing Ki-67. These findings suggest that PBF TCR-T cell therapy might be a candidate immunotherapy for sarcoma highly expressing PBF.

    DOI: 10.1111/cas.15967

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  • Restoration of ARID1A Protein in ARID1A-deficient Clear Cell Carcinoma of the Ovary Attenuates Reactivity to Cytotoxic T Lymphocytes. 国際誌

    Risa Tsunematsu, Aiko Murai, Yuka Mizue, Terufumi Kubo, Tasuku Mariya, Rena Morita, Kenji Murata, Takayuki Kanaseki, Tomohide Tsukahara, Yoshihiko Hirohashi, Tsuyoshi Saito, Toshihiko Torigoe

    Cancer genomics & proteomics   21 ( 4 )   414 - 420   2024年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND/AIM: Clear cell carcinoma is a prevalent histological type of ovarian cancer in East Asia, particularly in Japan, known for its resistance to chemotherapeutic agents and poor prognosis. ARID1A gene mutations, commonly found in ovarian clear cell carcinoma (OCCC), contribute to its pathogenesis. Recent data revealed that the ARID1A mutation is related to better outcomes of cancer immunotherapy. Thus, this study aimed to investigate the immunotherapy treatment susceptibility of OCCC bearing ARID1A mutations. MATERIALS AND METHODS: Expression of ARID1A was analyzed using western blotting in ovarian cancer cell lines. OCCC cell lines JHOC-9 and RMG-V were engineered to overexpress NY-ESO-1, HLA-A*02:01, and ARID1A. Sensitivity to chemotherapy and T cell receptor-transduced T (TCR-T) cells specific for NY-ESO-1 was assessed in ARID1A-restored cells compared to ARID1A-deficient wild-type cells. RESULTS: JHOC-9 cells and RMG-V cells showed no expression of ARID1A protein. Overexpression of ARID1A in JHOC-9 and RMG-V cells did not impact sensitivity to gemcitabine. While ARID1A overexpression decreased sensitivity to cisplatin in RMG-V cells, it had no such effect in JHOC-9 cells. ARID1A overexpression reduced the reactivity of NY-ESO-1-specific TCR-T cells, as observed by the IFNγ ESLIPOT assay. CONCLUSION: Cancer immunotherapy is an effective approach to target ARID1A-deficient clear cell carcinoma of the ovary.

    DOI: 10.21873/cgp.20460

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  • Eribulin is an immune potentiator in breast cancer that upregulates human leukocyte antigen class I expression via the induction of NOD-like receptor family CARD domain-containing 5. 国際誌

    Asaka Wada, Yoshihiko Hirohashi, Goro Kutomi, Kenji Murata, Sadahiro Iwabuchi, Yuka Mizue, Aiko Murai, Daisuke Kyuno, Hiroaki Shima, Tomoyuki Minowa, Kenta Sasaki, Terufumi Kubo, Takayuki Kanaseki, Tomohide Tsukahara, Munehide Nakatsugawa, Shinichi Hashimoto, Makoto Osanai, Toshihiko Torigoe, Ichiro Takemasa

    Cancer science   114 ( 12 )   4511 - 4520   2023年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Eribulin inhibits microtubule polymerization and improves the overall survival of patients with recurrent metastatic breast cancer. A subgroup analysis revealed a low neutrophil to lymphocyte ratio (NLR) (<3) to be a prognostic factor of eribulin treatment. We thus hypothesized that eribulin might be related to the immune response for breast cancer cells and we analyzed the effects of eribulin on the immune system. Immunohistochemical staining revealed that human leukocyte antigen (HLA) class I expression was increased in clinical samples after eribulin treatment. In vitro assays revealed that eribulin treatment increased HLA class I expression in breast cancer line cells. RNA-sequencing demonstrated that eribulin treatment increased the expression of the NOD-like family CARD domain-containing 5 (NLRC5), a master regulator of HLA class I expression. Eribulin treatment increased the NY-ESO-1-specific T-cell receptor (TCR) transduced T (TCR-T) cell response for New York oesophageal squamous cell carcinoma 1 (NY-ESO-1) overexpressed breast cancer cells. The eribulin and TCR-T combined therapy model revealed that eribulin and immunotherapy using TCR-T cells has a synergistic effect. In summary, eribulin increases the expression of HLA class 1 via HLA class 1 transactivatior NLRC5 and eribulin combination with immunotherapy can be effective for the treatment of breast cancer.

    DOI: 10.1111/cas.15986

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  • Establishment and characterization of a novel dedifferentiated chondrosarcoma cell line, SMU-DDCS, harboring an IDH1 mutation

    Makoto Emori, Naoya Nakahashi, Akira Takasawa, Kenji Murata, Yasutaka Murahashi, Junya Shimizu, Tomohide Tsukahara, Shintaro Sugita, Kohichi Takada, Tadashi Hasegawa, Makoto Osanai, Kosuke Iba

    Human Cell   2023年7月

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

    その他リンク: https://link.springer.com/article/10.1007/s13577-023-00944-0/fulltext.html

    DOI: 10.1007/s13577-023-00944-0

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  • Metastatic pulmonary pleomorphic carcinoma replaced by a granulomatous lesion after spontaneous regression and PD-1 blockade-induced regression: can epithelioid granuloma be a histological hallmark of cancer immunity? 国際誌

    Naoki Shijubou, Yuichiro Asai, Michiko Hosaka, Keiko Segawa, Terufumi Kubo, Masahiro Miyajima, Tomohide Tsukahara, Yoshihiko Hirohashi, Takayuki Kanaseki, Kenji Murata, Atsushi Watanabe, Tadashi Hasegawa, Hirofumi Chiba, Toshihiko Torigoe

    Immunological medicine   46 ( 2 )   93 - 96   2023年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Immune checkpoint inhibitors (ICIs) for various types of malignancy, including non-small-cell lung cancer, have improved prognosis in some cases. Granuloma formation after ICI administration suggests a tumor antigen-specific cytotoxic T cell response with abundant interferon-gamma production, which can be used to estimate the curative effect of ICIs. In this report, we present a case with a resected lung lesion, clinically suspected to be lung cancer, that consisted of a granulomatous lesion. A tumor was also found in the duodenum that was presumed to be derived from the pulmonary pleomorphic carcinoma. Duodenal tumor cells highly expressed PD-L1, suggesting PD-1/PD-L1 axis-mediated immune escape. As expected, pembrolizumab induced a complete response for the duodenal lesion. Interestingly, in histopathological analysis, the duodenal lesion was also replaced by an epithelial granuloma and multinucleated giant cells. We conclude that autoimmunity regressed the untreated primary lung lesion spontaneously, while the metastatic duodenal lesion responded to PD-1 blockade. Tumor-associated epithelioid granulomas, even before ICI administration, may be an important pathological finding indicating an immune response with interferon-gamma production by cytotoxic T cells to the tumor.

    DOI: 10.1080/25785826.2023.2193283

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  • Fusion with type 2 macrophages induces melanoma cell heterogeneity that potentiates immunological escape from cytotoxic T lymphocytes. 国際誌

    Tomoyuki Minowa, Yoshihiko Hirohashi, Kenji Murata, Kenta Sasaki, Toshiya Handa, Munehide Nakatsugawa, Yuka Mizue, Aiko Murai, Terufumi Kubo, Takayuki Kanaseki, Tomohide Tsukahara, Sadahiro Iwabuchi, Shinichi Hashimoto, Akemi Ishida-Yamamoto, Hisashi Uhara, Toshihiko Torigoe

    The Journal of pathology   260 ( 3 )   304 - 316   2023年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Evasion from immunity is a major obstacle to the achievement of successful cancer immunotherapy. Hybrids derived from cell-cell fusion are theoretically associated with tumor heterogeneity and progression by conferring novel properties on tumor cells, including drug resistance and metastatic capacity; however, their impact on immune evasion remains unknown. Here, we investigated the potency of tumor-macrophage hybrids in immune evasion. Hybrids were established by co-culture of a melanoma cell line (A375 cells) and type 2 macrophages. The hybrids showed greater migration ability and greater tumorigenicity than the parental melanoma cells. The hybrids showed heterogeneous sensitivity to New York esophageal squamous cell carcinoma-1 (NY-ESO-1)-specific T-cell receptor-transduced T (TCR-T) cells and two out of four hybrid clones showed less sensitivity to TCR-T compared with the parental cells. An in vitro tumor heterogeneity model revealed that the TCR-T cells preferentially killed the parental cells compared with the hybrids and the survival rate of the hybrids was higher than that of the parental cells, indicating that the hybrids evade killing by TCR-T cells efficiently. Analysis of a single-cell RNA sequencing dataset of patients with melanoma revealed that a few macrophages expressed RNA encoding melanoma differentiation antigens including melan A, tyrosinase, and premelanosome protein, which indicated the presence of hybrids in primary melanoma. In addition, the number of potential hybrids was correlated with a poorer response to immune checkpoint blockade. These results provide evidence that melanoma-macrophage fusion has a role in tumor heterogeneity and immune evasion. © 2023 The Pathological Society of Great Britain and Ireland.

    DOI: 10.1002/path.6083

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  • SOX10 Inhibits T Cell Recognition by Inducing Expression of the Immune Checkpoint Molecule PD-L1 in A375 Melanoma Cells. 国際誌

    Kenta Sasaki, Yoshihiko Hirohashi, Kenji Murata, Tomoyuki Minowa, Munehide Nakatsugawa, Aiko Murai, Yuka Mizue, Terufumi Kubo, Takayuki Kanaseki, Tomohide Tsukahara, Sadahiro Iwabuchi, Shinichi Hashimoto, Hisashi Uhara, Akemi Ishida-Yamamoto, Toshihiko Torigoe

    Anticancer research   43 ( 4 )   1477 - 1484   2023年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND/AIM: Malignant melanoma is a fatal skin cancer and is among the most immunogenic malignancies expressing melanoma-differentiation antigens and neoantigens. SRY-related HMG-box 10 (SOX10) is a transcription factor and a neural-crest differentiation marker that is used as a diagnostic marker for melanoma whilst playing a role in melanoma initiation through activation of the SOX10-MITF axis. SOX10 was shown to play a role in melanoma initiation by inducing expression of immune checkpoint molecules (e.g., HVEM and CEACAM1). In this study, we aimed to investigate the relationship between SOX10 and the expression an immune checkpoint molecule, programmed death-1 ligand 1 (PD-L1). MATERIALS AND METHODS: SOX10 overexpression and knockdown was performed using SOX10 gene transfection and SOX10 siRNA transfection into A375 melanoma cells. PD-L1 expression was assessed by flow cytometry and western blotting. T cell response was evaluated using NY-ESO-1 specific TCR-transduced T (TCR-T) cells by IFNγ ELISPOT assay. RESULTS: SOX10 overexpression increased the expression of PD-L1, whereas SOX10 knockdown, using siRNA, decreased its expression. IFNγ ELISPOT assay revealed that overexpression of SOX10 decreased the susceptibility of cells to NY-ESO-1-specific TCR-T cells. CONCLUSION: SOX10 has a role in the intrinsic immune suppressive mechanisms of melanoma through expression of PD-L1.

    DOI: 10.21873/anticanres.16296

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  • Development of CAR-T cells specifically targeting cancer stem cell antigen DNAJB8 against solid tumours. 国際誌

    Yuto Watanabe, Tomohide Tsukahara, Kenji Murata, Shuto Hamada, Terufumi Kubo, Takayuki Kanaseki, Yoshihiko Hirohashi, Makoto Emori, Atsushi Teramoto, Munehide Nakatsugawa, Toshihiko Yamashita, Toshihiko Torigoe

    British journal of cancer   128 ( 5 )   886 - 895   2023年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: As therapy for solid tumours, various tumour antigens have been selected as targets, but CAR-T cells targeting these antigens have shown limited efficacy, in contrast to the effectiveness of CAR-T cells targeting haematological malignancies. In a previous report, we identified a cancer-testis antigen, DNAJB8. DNAJB8 plays a major role in tumorigenicity in cancer stem-like cells/cancer-initiating cells (CSCs/CICs). Here, we report a DNAJB8-reactive CAR yielding anti-tumour effects against renal cell carcinoma (RCC) and osteosarcoma. METHODS: We constructed a second-generation chimeric antigen receptor (CAR) against HLA-A*24:02/DNAJB8-derived peptide (DNAJB_143) complex (B10 CAR). The reactivity of B10-CAR T cells against T2-A24 cells pulsed with the cognate peptide and an RCC and osteosarcoma cell lines were quantified. The effects of adoptive cell transfer (ACT) therapy were assessed using in vivo xenografted mice models. RESULTS: B10 CAR-T cells recognised DNAJB8_143-pulsed T2-A24 cells and HLA-A*24:02(+)/DNAJB8(+) renal cell carcinoma and osteosarcoma cell lines. Moreover, ACT using B10 CAR-T cells showed anti-tumour effects against RCC and osteosarcoma cells. CONCLUSION: B10 CAR-T cells could show specific cytotoxicity against RCC and osteosarcoma cells in vitro and in vivo. B10 CAR-T cells targeting the CSC/CIC antigen DNAJB8 might be a candidate immunotherapy for carcinoma and sarcoma.

    DOI: 10.1038/s41416-022-02100-1

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  • Cisplatin resistance driver claspin is a target for immunotherapy in urothelial carcinoma. 国際誌

    Shuhei Yamada, Haruka Miyata, Makoto Isono, Kanta Hori, Junko Yanagawa, Aiko Murai, Tomoyuki Minowa, Yuka Mizue, Kenta Sasaki, Kenji Murata, Serina Tokita, Munehide Nakatsugawa, Sadahiro Iwabuchi, Shinichi Hashimoto, Terufumi Kubo, Takayuki Kanaseki, Tomohide Tsukahara, Takashige Abe, Nobuo Shinohara, Yoshihiko Hirohashi, Toshihiko Torigoe

    Cancer immunology, immunotherapy : CII   72 ( 7 )   2057 - 2065   2023年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Bladder cancer is a major and fatal urological disease. Cisplatin is a key drug for the treatment of bladder cancer, especially in muscle-invasive cases. In most cases of bladder cancer, cisplatin is effective; however, resistance to cisplatin has a significant negative impact on prognosis. Thus, a treatment strategy for cisplatin-resistant bladder cancer is essential to improve the prognosis. In this study, we established a cisplatin-resistant (CR) bladder cancer cell line using an urothelial carcinoma cell lines (UM-UC-3 and J82). We screened for potential targets in CR cells and found that claspin (CLSPN) was overexpressed. CLSPN mRNA knockdown revealed that CLSPN had a role in cisplatin resistance in CR cells. In our previous study, we identified human leukocyte antigen (HLA)-A*02:01-restricted CLSPN peptide by HLA ligandome analysis. Thus, we generated a CLSPN peptide-specific cytotoxic T lymphocyte clone that recognized CR cells at a higher level than wild-type UM-UC-3 cells. These findings indicate that CLSPN is a driver of cisplatin resistance and CLSPN peptide-specific immunotherapy may be effective for cisplatin-resistant cases.

    DOI: 10.1007/s00262-023-03388-5

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  • Cisplatin-induced HSF1-HSP90 axis enhances the expression of functional PD-L1 in oral squamous cell carcinoma. 国際誌

    Takashi Sasaya, Terufumi Kubo, Kenji Murata, Yuka Mizue, Kenta Sasaki, Junko Yanagawa, Makoto Imagawa, Hirotaka Kato, Tomohide Tsukahara, Takayuki Kanaseki, Yasuaki Tamura, Akihiro Miyazaki, Yoshihiko Hirohashi, Toshihiko Torigoe

    Cancer medicine   12 ( 4 )   4605 - 4615   2023年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Immune checkpoint inhibitor-based cancer immunotherapy has provided an additional therapeutic option for oral squamous cell carcinoma (OSCC) with recurrence or distant metastases. However, further improvement of OSCC treatment is required to develop the optimal combination or order for chemoradiotherapy and immunotherapy. Along with the accumulation of clinical knowledge and evidence, it is also essential to clarify the biological impact of chemo-radiotherapeutic agents on the cancer immune microenvironment. In this study, we investigated the effects of cisplatin (CDDP), a key therapeutic agent for OSCC, on programmed death-ligand 1 (PD-L1) expression in OSCC lines. Although CDDP treatment increased the surface levels of PD-L1 on OSCC cell lines, the gene and total protein expression levels of PD-L1 were not altered. We also demonstrated that the phosphorylation of heat shock factor 1 and heat shock protein 90 was involved in this process. In addition, CDDP-induced PD-L1 attenuated the target-specific cytotoxic T lymphocyte reaction to OSCC. These results provide an immunobiological basis for the response of OSCC to CDDP and will contribute to our biological understanding of the action of novel combination therapy including immunotherapy together with platinum-based chemotherapy for OSCC.

    DOI: 10.1002/cam4.5310

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  • Modification of the HLA-A*24:02 Peptide Binding Pocket Enhances Cognate Peptide-Binding Capacity and Antigen-Specific T Cell Activation. 国際誌

    Kenji Murata, Dalam Ly, Hiroshi Saijo, Yukiko Matsunaga, Kenji Sugata, Fumie Ihara, Daisuke Oryoji, Yota Ohashi, Kayoko Saso, Chung-Hsi Wang, Evey Y F Zheng, Brian D Burt, Marcus O Butler, Naoto Hirano

    Journal of immunology (Baltimore, Md. : 1950)   209 ( 8 )   1481 - 1491   2022年9月

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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)  

    The immunogenicity of a T cell Ag is correlated with the ability of its antigenic epitope to bind HLA and be stably presented to T cells. This presents a challenge for the development of effective cancer immunotherapies, as many self-derived tumor-associated epitopes elicit weak T cell responses, in part due to weak binding affinity to HLA. Traditional methods to increase peptide-HLA binding affinity involve modifying the peptide to reflect HLA allele binding preferences. Using a different approach, we sought to analyze whether the immunogenicity of wild-type peptides could be altered through modification of the HLA binding pocket. After analyzing HLA class I peptide binding pocket alignments, we identified an alanine 81 to leucine (A81L) modification within the F binding pocket of HLA-A*24:02 that was found to heighten the ability of artificial APCs to retain and present HLA-A*24:02-restricted peptides, resulting in increased T cell responses while retaining Ag specificity. This modification led to increased peptide exchange efficiencies for enhanced detection of low-avidity T cells and, when expressed on artificial APCs, resulted in greater expansion of Ag-specific T cells from melanoma-derived tumor-infiltrating lymphocytes. Our study provides an example of how modifications to the HLA binding pocket can enhance wild-type cognate peptide presentation to heighten T cell activation.

    DOI: 10.4049/jimmunol.2200305

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  • Characterization of Proteasome-Generated Spliced Peptides Detected by Mass Spectrometry. 国際誌

    Koji Kato, Munehide Nakatsugawa, Serina Tokita, Yoshihiko Hirohashi, Terufumi Kubo, Tomohide Tsukahara, Kenji Murata, Hirofumi Chiba, Hiroki Takahashi, Naoto Hirano, Takayuki Kanaseki, Toshihiko Torigoe

    Journal of immunology (Baltimore, Md. : 1950)   208 ( 12 )   2856 - 2865   2022年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    CD8+ T cells recognize peptides displayed by HLA class I molecules and monitor intracellular peptide pools. It is known that the proteasome splices two short peptide fragments. Recent studies using mass spectrometry (MS) and bioinformatics analysis have suggested that proteasome-generated spliced peptides (PSPs) may account for a substantial proportion of HLA class I ligands. However, the authenticity of the PSPs identified using bioinformatics approaches remain ambiguous. In this study, we employed MS-based de novo sequencing to directly capture cryptic HLA ligands that were not templated in the genome. We identified two PSPs originating from the same protein in a human colorectal cancer line with microsatellite instability. Healthy donor-derived CD8+ T cells readily responded to the two PSPs, showing their natural HLA presentation and antigenicity. Experiments using minigene constructs demonstrated proteasome-dependent processing of two PSPs generated by standard and reverse cis splicing, respectively. Our results suggest a broader diversity of HLA class I Ag repertoires generated by proteasomal splicing, supporting the advantage of MS-based approaches for the comprehensive identification of PSPs.

    DOI: 10.4049/jimmunol.2100717

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  • Tumor-infiltrating CD8+ T cells recognize a heterogeneously expressed functional neoantigen in clear cell renal cell carcinoma. 国際誌

    Masahiro Matsuki, Yoshihiko Hirohashi, Munehide Nakatsugawa, Aiko Murai, Terufumi Kubo, Shinichi Hashimoto, Serina Tokita, Kenji Murata, Takayuki Kanaseki, Tomohide Tsukahara, Sachiyo Nishida, Toshiaki Tanaka, Hiroshi Kitamura, Naoya Masumori, Toshihiko Torigoe

    Cancer immunology, immunotherapy : CII   71 ( 4 )   905 - 918   2022年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Immune checkpoint inhibitors (ICIs) are used in cancer immunotherapy to block programmed death-1 and cytotoxic T-lymphocyte antigen 4, but the response rate for ICIs is still low and tumor cell heterogeneity is considered to be responsible for resistance to immunotherapy. Tumor-infiltrating lymphocytes (TILs) have an essential role in the anti-tumor effect of cancer immunotherapy; however, the specificity of TILs in renal cell carcinoma (RCC) is elusive. In this study, we analyzed a 58-year-old case with clear cell RCC (ccRCC) with the tumor showing macroscopic and microscopic heterogeneity. The tumor was composed of low-grade and high-grade ccRCC. A tumor cell line (1226 RCC cells) and TILs were isolated from the high-grade ccRCC lesion, and a TIL clone recognized a novel neoantigen peptide (YVVPGSPCL) encoded by a missense mutation of the tensin 1 (TNS1) gene in a human leukocyte antigen-C*03:03-restricted fashion. The TNS1 gene mutation was not detected in the low-grade ccRCC lesion and the TIL clone did not recognized low-grade ccRCC cells. The missense mutation of TNS1 encoding the S1309Y mutation was found to be related to cell migration by gene over-expression. These findings suggest that macroscopically and microscopically heterogenous tumors might show heterogenous gene mutations and reactivity to TILs.

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  • High aldehyde dehydrogenase 1 activity is related to radiation resistance due to activation of AKT signaling after insulin stimulation in prostate cancer. 国際誌

    Takahito Wakamiya, Yoshihiko Hirohashi, Aiko Murai, Junko Yanagawa, Yuka Mizue, Terufumi Kubo, Shinichi Hashimoto, Kenji Murata, Takayuki Kanaseki, Tomohide Tsukahara, Sachiyo Nishida, Yasuo Kohjimoto, Isao Hara, Toshihiko Torigoe

    Biochemical and biophysical research communications   590   117 - 124   2022年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The association between type 2 diabetes mellitus and prostate cancer is still under investigation, and the relationship between hyperinsulinemia and prostate cancer stem-like cells (CSCs) is elusive. Here, we investigated the function of insulin/AKT signaling in prostate CSCs. We isolated prostate CSCs as aldehyde dehydrogenase 1-high (ALDH1high) cells from the human prostate cancer 22Rv1 cell line using an ALDEFLUOR assay and established several ALDH1high and ALDH1low clones. ALDH1high clones showed high ALDH1 expression which is a putative CSC marker; however, they showed heterogeneity regarding tumorigenicity and resistance to radiation and chemotherapy. Interestingly, all ALDH1high clones showed lower phosphorylated AKT (Ser473) (pAKT) levels than the ALDH1low clones. PI3K/AKT signaling is a key cell survival pathway and we analyzed radiation resistance under AKT signaling activation by insulin. Insulin increased pAKT levels in ALDH1high and ALDH1low cells; the fold increase rate of pAKT was higher in ALDH1high cells than in ALDH1low cells. Insulin induced resistance to radiation and chemotherapy in ALDH1high cells, and the increased levels of pAKT induced by insulin were significantly related to radiation resistance. These results suggest that ALDH1 suppresses baseline pAKT levels, but AKT can be activated by insulin, leading to treatment resistance.

    DOI: 10.1016/j.bbrc.2021.12.095

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  • Immunopathological basis of immune-related adverse events induced by immune checkpoint blockade therapy. 国際誌

    Terufumi Kubo, Yoshihiko Hirohashi, Tomohide Tsukahara, Takayuki Kanaseki, Kenji Murata, Rena Morita, Toshihiko Torigoe

    Immunological medicine   45 ( 2 )   1 - 11   2021年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Despite the considerable success of cancer immunotherapy with immune checkpoint inhibitors, their nonspecific release of the immunosuppressive mechanism is often associated with immune-related adverse events (irAEs). irAEs significantly disturb patients' quality of life and can even be life-threatening. Therefore, the appropriate management of irAEs is crucial for the development of further reliable cancer immunotherapies. irAEs have the appearance of ordinary autoimmune diseases in one aspect but often have distinct features. Although the detailed pathogenesis of irAEs remains unclear, increasing numbers of studies have provided numerous clues. Here, we review the current knowledge on irAEs, particularly from an immunopathological basis.

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  • IL-13 modulates ∆Np63 levels causing altered expression of barrier- and inflammation-related molecules in human keratinocytes: A possible explanation for chronicity of atopic dermatitis. 国際誌

    Terufumi Kubo, Sayuri Sato, Tokimasa Hida, Tomoyuki Minowa, Yoshihiko Hirohashi, Tomohide Tsukahara, Takayuki Kanaseki, Kenji Murata, Hisashi Uhara, Toshihiko Torigoe

    Immunity, inflammation and disease   9 ( 3 )   734 - 745   2021年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Barrier disruption and an excessive immune response in keratinocytes are now considered to have important roles in the pathophysiology of atopic dermatitis (AD). Furthermore, disturbed keratinocyte differentiation is considered to underlie AD. ΔNp63, a p53-like transcription factor, is a major regulator of keratinocyte differentiation. However, the functional significance of ΔNp63 in AD has not been clarified. OBJECTIVE: In this study, we aimed to investigate the influence of the type 2 inflammatory environment on ΔNp63 expression and AD-associated molecules regulated by ΔNp63 in keratinocytes. METHODS: The immunohistochemical expression profiles of ΔNp63 and AD-related molecules were evaluated in human skin tissue. The function of ΔNp63 in the regulation of AD-related molecules and the influence of the type 2 inflammatory environment on ΔNp63 expression were investigated using human primary keratinocytes. Expression of ΔNp63 was manipulated using the RNA interfering method. RESULTS: In healthy skin tissue, we observed an inverse expression pattern between ∆Np63 and some barrier-related proteins including filaggrin, caspase-14, claudin-1, and claudin-4. ΔNp63 regulated expression of these genes and proteins. In addition, production of IL-1β and IL-33, pro-inflammatory cytokines, was modulated by ΔNp63. Furthermore, prolonged IL-13 exposure increased the thickness of the three-dimensional culture of keratinocytes. IL-13 interfered with ΔNp63 downregulation during calcium-induced keratinocyte differentiation. IL-13 modulated some barrier-related and inflammation-related molecules, which were regulated by ΔNp63. CONCLUSIONS: We have shown that ΔNp63 modulated AD-related barrier and inflammatory molecules. In addition, ΔNp63 expression was affected by IL-4/IL-13. IL-13-ΔNp63 axis would integrate two major factors of AD pathogenesis: dysregulated barrier and inflammation.

    DOI: 10.1002/iid3.427

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  • Affinity-matured HLA class II dimers for robust staining of antigen-specific CD4+ T cells. 国際誌

    Kenji Sugata, Yukiko Matsunaga, Yuki Yamashita, Munehide Nakatsugawa, Tingxi Guo, Levon Halabelian, Yota Ohashi, Kayoko Saso, Muhammed A Rahman, Mark Anczurowski, Chung-Hsi Wang, Kenji Murata, Hiroshi Saijo, Yuki Kagoya, Dalam Ly, Brian D Burt, Marcus O Butler, Tak W Mak, Naoto Hirano

    Nature biotechnology   39 ( 8 )   958 - 967   2021年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Peptide-major histocompatibility complex (pMHC) multimers enable the detection of antigen-specific T cells in studies ranging from vaccine efficacy to cancer immunotherapy. However, this technology is unreliable when applied to pMHC class II for the detection of CD4+ T cells. Here, using a combination of molecular biological and immunological techniques, we cloned sequences encoding human leukocyte antigen (HLA)-DP, HLA-DQ and HLA-DR molecules with enhanced CD4 binding affinity (with a Kd of 8.9 ± 1.1 µM between CD4 and affinity-matured HLA-DP4) and produced affinity-matured class II dimers that stain antigen-specific T cells better than conventional multimers in both in vitro and ex vivo analyses. Using a comprehensive library of dimers for HLA-DP4, which is the most frequent HLA allele in many ancestry groups, we mapped 103 HLA-DP4-restricted epitopes derived from diverse tumor-associated antigens and cloned the cognate T-cell antigen receptor (TCR) genes from in vitro-stimulated CD4+ T cells. The availability of affinity-matured class II dimers across HLA-DP, HLA-DQ and HLA-DR alleles will aid in the investigation of human CD4+ T-cell responses.

    DOI: 10.1038/s41587-021-00836-4

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  • Proteogenomic identification of an immunogenic HLA class I neoantigen in mismatch repair-deficient colorectal cancer tissue. 国際誌

    Tomomi Hirama, Serina Tokita, Munehide Nakatsugawa, Kenji Murata, Yasuhito Nannya, Kazuhiko Matsuo, Hidetoshi Inoko, Yoshihiko Hirohashi, Shinichi Hashimoto, Seishi Ogawa, Ichiro Takemasa, Noriyuki Sato, Fumitake Hata, Takayuki Kanaseki, Toshihiko Torigoe

    JCI insight   6 ( 14 )   2021年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Although CD8+ T cells recognize neoantigens that arise from somatic mutations in cancer, only a small fraction of nonsynonymous mutations give rise to clinically relevant neoantigens. In this study, HLA class I ligandomes of a panel of human colorectal cancer (CRC) and matched normal tissues were analyzed using mass spectrometry-based proteogenomic analysis. Neoantigen presentation was rare; however, the analysis detected a single neoantigen in a mismatch repair-deficient CRC (dMMR-CRC) tissue sample carrying 3967 nonsynonymous mutations, where abundant tumor-infiltrating lymphocytes (TILs) and inflamed gene expression status were observed in the tumor microenvironment (TME). Using the HLA class I ligandome data and gene expression profiles, a set of nonmutated tumor-associated antigen (TAA) candidates was concomitantly identified. Interestingly, CD8+ TILs predominantly recognized the detected neoantigen over the array of TAA candidates. Neoantigen-reactive CD8+ TILs showed PD-1 positivity and exhibited functional and specific responses. Moreover, T cell receptor (TCR) profiling identified the sequence of the neoantigen-reactive TCR clonotype and showed its expansion in the TME. Transduction of the sequenced TCR conferred neoantigen specificity and cytotoxicity to peripheral blood lymphocytes. The proteogenomic approach revealed the antigenic and reactive T cell landscape in dMMR-CRC, demonstrating the presence of an immunogenic neoantigen and its potential therapeutic applications.

    DOI: 10.1172/jci.insight.146356

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  • Epithelioid granulomatous lesions express abundant programmed death ligand-1 (PD-L1): a discussion of adverse events in anti-PD-1 antibody-based cancer immunotherapy. 国際誌

    Terufumi Kubo, Yoshihiko Hirohashi, Tomohide Tsukahara, Takayuki Kanaseki, Kenji Murata, Tadashi Hasegawa, Toshihiko Torigoe

    Human vaccines & immunotherapeutics   17 ( 7 )   1940 - 1942   2021年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The immune system is often called a double-edged sword, due to the inextricable link between cancer immunity and allergy/autoimmunity. Intriguingly, a growing number of cases have been reported in which PD-1 blockade triggers the exacerbation of tuberculosis (TB), an organ-invasive granulomatous disease caused by bacterial infection. As a result, the exacerbation of TB is now considered a severe adverse effect of nivolumab and pembrolizumab. In this letter, we report the strong expression of PD-L1 in epithelioid granulomatous lesions in tuberculosis, sarcoidosis, Crohn's disease, and foreign body granuloma. In addition, we discussed the exacerbation of tuberculosis after anti-PD-1 antibody-based cancer immunotherapy.

    DOI: 10.1080/21645515.2020.1870364

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  • Neuregulin-1-β1 and γ-secretase play a critical role in sphere-formation and cell survival of urothelial carcinoma cancer stem-like cells. 国際誌

    Masahiro Matsuki, Ryuta Inoue, Aiko Murai, Terufumi Kubo, Shinichi Hashimoto, Kenji Murata, Takayuki Kanaseki, Tomohide Tsukahara, Sachiyo Nishida, Toshiaki Tanaka, Hiroshi Kitamura, Naoya Masumori, Yoshihiko Hirohashi, Toshihiko Torigoe

    Biochemical and biophysical research communications   552   128 - 135   2021年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Previously, we investigated gene expression in a high aldehyde dehydrogenase 1 expression (ALDH1high) population of urothelial carcinoma (UC) cells as UC cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) and found that NRG1 expression was upregulated in ALDH1high cells. NRG1 is a trophic factor that contains an epidermal growth factor (EGF)-like domain that signals by stimulating ERBB receptor tyrosine kinases and the cytoplasmic domain. NRG1 has been determined to be involved in frequent gene fusions with other partners in several malignancies and has a role in carcinogenesis through the NRG1 EGF-like domain and its cognitive receptor ERBBs. We thus aimed to elucidate the function of NRG1 in UC CSCs/CICs in this study. Both NRG1α and NRG1-β1 were preferentially expressed in ALDH1high cells compared with ALDH1low cells; however, siRNA experiments revealed that NRG1-β1 but not NRG1-α has a role in sphere formation. The EGF-like domain of NRG1 had a role in sphere formation of UC cells to some extent but was not essential. The intracellular domain of NRG1 did not have a role in sphere-formation. Inhibition of γ-secretase suppressed sphere formation. These findings indicate that cleavage of NRG1-β1 by γ-secretase plays an important role in UC CSC/CIC proliferation; however, the downstream targets of NRG1-β1 remain elusive.

    DOI: 10.1016/j.bbrc.2021.03.038

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  • Changing the landscape of tumor immunology: novel tools to examine T cell specificity. 国際誌

    Muhammed A Rahman, Kenji Murata, Brian D Burt, Naoto Hirano

    Current opinion in immunology   69   1 - 9   2021年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Immunotherapy has established itself as a stalwart arm in patient care and with precision medicine forms the new paradigm in cancer treatment. T cells are an important group of immune cells capable of potent cancer immune surveillance and immunity. The advent of bioinformatics, particularly more recent advances incorporating algorithms employing machine learning, provide a seemingly limitless ability for T cell analysis and hypothesis generation. Such endeavors have become indispensable to research efforts accelerating and evolving to such an extent that there exists an appreciable gap between knowledge and proof of function and application. Exciting new technologies such as DNA barcoding, cytometry by time-of-flight (CyTOF), and peptide-exchangeable pHLA multimers inclusive of rare and difficult HLA alleles offer high-throughput cell-by-cell analytical capabilities. These outstanding recent contributions to T cell research will help close this gap and potentially bring practical benefit to patients.

    DOI: 10.1016/j.coi.2020.11.003

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  • Identification of characteristic subepithelial surface granulomatosis in immune-related adverse event-associated enterocolitis. 国際誌

    Terufumi Kubo, Yoshihiko Hirohashi, Yoshiko Keira, Mayuko Akimoto, Tatsuru Ikeda, Noriaki Kikuchi, Hiroyuki Iwaki, Tomoki Kikuchi, Masahiko Obata, Rena Morita, Kiyoshi Kasai, Keiko Segawa, Tomohide Tsukahara, Takayuki Kanaseki, Kenji Murata, Yasuhiro Kikuchi, Tomoyo Shinkawa, Tadashi Hasegawa, Toshihiko Torigoe

    Cancer science   112 ( 3 )   1320 - 1325   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Immune checkpoint inhibitors (ICIs) have provided an additional treatment option for various types of human cancers. However, ICIs often induce various immune-related adverse events (irAEs). Enterocolitis is a major irAE with poorly understood histopathological characteristics. In this study, we retrospectively investigated the histopathology of colon tissue samples from 17 patients treated with ICIs. There were two major histological patterns of colitis: an ulcerative colitis-like pattern and a graft vs host disease-like pattern. Although these two patterns of colitis were mutually exclusive, both patterns often showed a characteristic that we call "subepithelial surface granulomatosis" (SSG), which has not been reported in other types of colitis. SSG was found even in colon tissue without symptoms or endoscopic findings of colitis. Given the increasing reports of sarcoid reaction or exacerbation of tuberculosis after treatment with ICIs, granuloma formation could be a histological hallmark of systemic immune activation by ICIs. Although statistical significance was not obtained, probably because of the small sample size, SSG may be a surrogate biomarker of systemic anticancer immune activation. We propose that a prospective study with larger sample size be performed.

    DOI: 10.1111/cas.14773

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  • Fundamental and Essential Knowledge for Pathologists Engaged in the Research and Practice of Immune Checkpoint Inhibitor-Based Cancer Immunotherapy. 国際誌

    Terufumi Kubo, Tomoyo Shinkawa, Yasuhiro Kikuchi, Kenji Murata, Takayuki Kanaseki, Tomohide Tsukahara, Yoshihiko Hirohashi, Toshihiko Torigoe

    Frontiers in oncology   11   679095 - 679095   2021年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Extensive research over 100 years has demonstrated that tumors can be eliminated by the autologous immune system. Without doubt, immunotherapy is now a standard treatment along with surgery, chemotherapy, and radiotherapy; however, the field of cancer immunotherapy is continuing to develop. The current challenges for the use of immunotherapy are to enhance its clinical efficacy, reduce side effects, and develop predictive biomarkers. Given that histopathological analysis provides molecular and morphological information on humans in vivo, its importance will continue to grow. This review article outlines the basic knowledge that is essential for the research and daily practice of immune checkpoint inhibitor-based cancer immunotherapy from the perspective of histopathology.

    DOI: 10.3389/fonc.2021.679095

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  • Genetic Ablation of HLA Class I, Class II, and the T-cell Receptor Enables Allogeneic T Cells to Be Used for Adoptive T-cell Therapy. 国際誌

    Yuki Kagoya, Tingxi Guo, Brian Yeung, Kayoko Saso, Mark Anczurowski, Chung-Hsi Wang, Kenji Murata, Kenji Sugata, Hiroshi Saijo, Yukiko Matsunaga, Yota Ohashi, Marcus O Butler, Naoto Hirano

    Cancer immunology research   8 ( 7 )   926 - 936   2020年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Adoptive immunotherapy can induce sustained therapeutic effects in some cancers. Antitumor T-cell grafts are often individually prepared in vitro from autologous T cells, which requires an intensive workload and increased costs. The quality of the generated T cells can also be variable, which affects the therapy's antitumor efficacy and toxicity. Standardized production of antitumor T-cell grafts from third-party donors will enable widespread use of this modality if allogeneic T-cell responses are effectively controlled. Here, we generated HLA class I, HLA class II, and T-cell receptor (TCR) triple-knockout (tKO) T cells by simultaneous knockout of the B2M, CIITA, and TRAC genes through Cas9/sgRNA ribonucleoprotein electroporation. Although HLA-deficient T cells were targeted by natural killer cells, they persisted better than HLA-sufficient T cells in the presence of allogeneic peripheral blood mononuclear cells (PBMC) in immunodeficient mice. When transduced with a CD19 chimeric antigen receptor (CAR) and stimulated by tumor cells, tKO CAR-T cells persisted better when cultured with allogeneic PBMCs compared with TRAC and B2M double-knockout T cells. The CD19 tKO CAR-T cells did not induce graft-versus-host disease but retained antitumor responses. These results demonstrated the benefit of HLA class I, HLA class II, and TCR deletion in enabling allogeneic-sourced T cells to be used for off-the-shelf adoptive immunotherapy.

    DOI: 10.1158/2326-6066.CIR-18-0508

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  • Peptide vaccinations elicited strong immune responses that were reboosted by anti-PD1 therapy in a patient with myxofibrosarcoma. 国際誌

    Tomohide Tsukahara, Kazue Watanabe, Kenji Murata, Akari Takahashi, Emi Mizushima, Yuji Shibayama, Hidekazu Kameshima, Ryo Hatae, Yasuo Ohno, Rituko Kawahara, Aiko Murai, Munehide Nakatsugawa, Terufumi Kubo, Takayuki Kanaseki, Yoshihiko Hirohashi, Takeshi Terui, Hiroko Asanuma, Tadashi Hasegawa, Noriyuki Sato, Toshihiko Torigoe

    Cancer immunology, immunotherapy : CII   69 ( 2 )   189 - 197   2020年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Peptide-based immunotherapy does not usually elicit strong immunological and clinical responses in patients with end-stage cancer, including sarcoma. Here we report a myxofibrosarcoma patient who showed a strong clinical response to peptide vaccinations and whose immune responses were reboosted by anti-PD1 therapy combined with peptide vaccinations. The 46-year-old man showed a strong response to the peptide vaccinations (papillomavirus binding factor peptide, survivin-2B peptide, incomplete Freund's adjuvant, and polyethylene glycol-conjugated interferon-alpha 2a) and subsequent wide necrosis and massive infiltration of CD8+ T cells in a recurrent tumor. The patient's immune responses weakened after surgical resection; however, they were reboosted following the administration of nivolumab combined with peptide vaccinations. Thus, anti-PD1 therapy combined with peptide vaccinations might be beneficial, as suggested by the observations in this sarcoma patient.

    DOI: 10.1007/s00262-019-02455-0

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  • Osteosarcoma-initiating cells show high aerobic glycolysis and attenuation of oxidative phosphorylation mediated by LIN28B. 国際誌

    Emi Mizushima, Tomohide Tsukahara, Makoto Emori, Kenji Murata, Asuka Akamatsu, Yuji Shibayama, Shuto Hamada, Yuto Watanabe, Mitsunori Kaya, Yoshihiko Hirohashi, Takayuki Kanaseki, Munehide Nakatsugawa, Terufumi Kubo, Toshihiko Yamashita, Noriyuki Sato, Toshihiko Torigoe

    Cancer science   111 ( 1 )   36 - 46   2020年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Osteosarcoma (OS) is a highly malignant bone tumor and the prognosis for non-responders to chemotherapy remains poor. Previous studies have shown that human sarcomas contain sarcoma-initiating cells (SIC), which have the characteristics of high tumorigenesis and resistance to chemotherapy. In the present study, we characterized SIC of a novel OS cell line, screened for SIC-related genes, and tried to regulate the proliferation of OS by metabolic interference. Initially, we established a new human OS cell line (OS13) and isolated clones showing higher tumorigenesis as SIC (OSHIGH ) and counterpart clones. OSHIGH cells showed chemoresistance and their metabolism highly depended on aerobic glycolysis and suppressed oxidative phosphorylation. Using RNA-sequencing, we identified LIN28B as a SIC-related gene highly expressed in OSHIGH cells. mRNA of LIN28B was expressed in sarcoma cell lines including OS13, but its expression was not detectable in normal organs other than the testis and placenta. LIN28B protein was also detected in various sarcoma tissues. Knockdown of LIN28B in OS13 cells reduced tumorigenesis, decreased chemoresistance, and reversed oxidative phosphorylation function. Combination therapy consisting of a glycolysis inhibitor and low-dose chemotherapy had antitumor effects. In conclusion, manipulation of glycolysis combined with chemotherapy might be a good adjuvant treatment for OS. Development of immunotherapy targeting LIN28B, a so-called cancer/testis antigen, might be a good approach.

    DOI: 10.1111/cas.14229

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  • Chaperones of the class I peptide-loading complex facilitate the constitutive presentation of endogenous antigens on HLA-DP84GGPM87. 国際誌

    Mark Anczurowski, Kenji Sugata, Yukiko Matsunaga, Yuki Yamashita, Chung-Hsi Wang, Tingxi Guo, Kenji Murata, Hiroshi Saijo, Yuki Kagoya, Kayoko Saso, Marcus O Butler, Naoto Hirano

    Journal of autoimmunity   102   114 - 125   2019年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Recent work has delineated key differences in the antigen processing and presentation mechanisms underlying HLA-DP alleles encoding glycine at position 84 of the DPβ chain (DP84GGPM87). These DPs are unable to associate with the class II-associated Ii peptide (CLIP) region of the invariant chain (Ii) chaperone early in the endocytic pathway, leading to continuous presentation of endogenous antigens. However, little is known about the chaperone support involved in the loading of these endogenous antigens onto DP molecules. Here, we demonstrate the proteasome and TAP dependency of this pathway and reveal the ability of HLA class I to compete with DP84GGPM87 for the presentation of endogenous antigens, suggesting that shared subcellular machinery may exist between the two classes of HLA. We identify physical interactions of prototypical class I-associated chaperones with numerous DP alleles, including TAP2, tapasin, ERp57, calnexin, and calreticulin, using a conventional immunoprecipitation and immunoblot approach and confirm the existence of these interactions in vivo through the use of the BioID2 proximal biotinylation system in human cells. Based on immunological assays, we then demonstrate the ability of each of these chaperones to facilitate the presentation of endogenously derived, but not exogenously derived, antigens on DP molecules. Considering previous genetic and clinical studies linking DP84GGPM87 to disease frequency and severity in autoimmune disease, viral infections, and cancer, we suggest that the above chaperones may form the molecular basis of these observable clinical differences through facilitating the presentation of endogenously derived antigens to CD4+ T cells.

    DOI: 10.1016/j.jaut.2019.04.023

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  • Arginine methylation of FOXP3 is crucial for the suppressive function of regulatory T cells. 国際誌

    Yuki Kagoya, Hiroshi Saijo, Yukiko Matsunaga, Tingxi Guo, Kayoko Saso, Mark Anczurowski, Chung-Hsi Wang, Kenji Sugata, Kenji Murata, Marcus O Butler, Cheryl H Arrowsmith, Naoto Hirano

    Journal of autoimmunity   97   10 - 21   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Forkhead box transcription factor 3 (FOXP3) plays a pivotal role in the suppressive function of regulatory T cells. In addition to mRNA levels, FOXP3 activity can also be controlled by posttranslational mechanisms, which have not been studied in a comprehensive manner. Through extensive screening using selective inhibitors, we demonstrate that the inhibition of type I protein arginine methytransferases (PRMTs) attenuates the suppressive functions of regulatory T cells. FOXP3 undergoes methylation on arginine residues at positions 48 and 51 by interacting with protein arginine methyltransferase 1 (PRMT1). The inhibition of arginine methylation confers gene expression profiles representing type I helper T cells to FOXP3+ T cells, which results in attenuated suppressive activity. A methylation-defective mutant of FOXP3 displays less potent activity to suppress xenogeneic graft-versus-host disease in vivo. These results elucidate an important role of arginine methylation to enhance FOXP3 functions and are potentially applicable to modulate regulatory T cell functions.

    DOI: 10.1016/j.jaut.2018.09.011

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  • Implication of chemo-resistant memory T cells for immune surveillance in patients with sarcoma receiving chemotherapy. 国際誌

    Yuji Shibayama, Tomohide Tsukahara, Makoto Emori, Kenji Murata, Emi Mizushima, Yoshihiko Hirohashi, Takayuki Kanaseki, Munehide Nakatsugawa, Terufumi Kubo, Toshihiko Yamashita, Noriyuki Sato, Toshihiko Torigoe

    Cancer science   108 ( 9 )   1739 - 1745   2017年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Chemotherapy has improved the prognosis of patients with sarcomas. However, it may suppress anti-tumor immunity. Recently, we reported a novel CD8+ memory T cell population with a chemo-resistance property, "young memory" T (TYM ) cells. In this study, we investigated the proportion and function of TYM cells in peripheral blood of healthy donors and sarcoma patients who received chemotherapy and those who did not. The proportion of TYM cells was significantly decreased in patients compared with that in healthy donors. In healthy donors, anti-EBV CTLs were induced using mixed lymphocyte peptide culture, from not only TYM cells but also TCM and TEM cells. No CTLs directed to tumor-associated antigens were induced. In sarcoma patients who did not receive chemotherapy, in addition to anti-EBV CTLs, CTLs directed to the tumor-associated antigen PBF were induced from TYM , TCM and TEM cells. In sarcoma patients who received chemotherapy, EBV-specific CTLs were induced from TYM cells but were hardly induced from TEM cells. Interestingly, CTLs directed to the anti-tumor-associated antigen PBF were induced from TYM cells but not from the TCM and TEM cells in sarcoma patients who received chemotherapy. The findings suggest that TYM cells are resistant to chemotherapy and can firstly recover from the nadir. TYM cells might be important for immunological memory, especially in sarcoma patients receiving chemotherapy.

    DOI: 10.1111/cas.13319

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  • The future of immunotherapy for sarcoma. 国際誌

    Tomohide Tsukahara, Makoto Emori, Kenji Murata, Emi Mizushima, Yuji Shibayama, Terufumi Kubo, Takayuki Kanaseki, Yoshihiko Hirohashi, Toshihiko Yamashita, Noriyuki Sato, Toshihiko Torigoe

    Expert opinion on biological therapy   16 ( 8 )   1049 - 57   2016年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    INTRODUCTION: The use of immunotherapeutic challenges for sarcoma has a long history. Despite the existence of objective responses, immunotherapy has been overshadowed by the results of chemotherapy, especially for osteosarcoma. However, the prognosis for non-responders to chemotherapy is still poor and immunotherapy is now focused on again. AREAS COVERED: We reviewed the following types of clinical trials of immunotherapy for sarcoma: (i) vaccination with autologous tumor cells, (ii) vaccination with peptides derived from tumor-associated antigens, (iii) adoptive cell transfer using engineered T cells expressing T cell receptor directed at NY-ESO-1 and (iv) immune checkpoint inhibitors targeting CTLA-4 and PD1/PDL1. EXPERT OPINION: The immunogenicity of sarcoma might be lower than that of melanoma. Patients with small lesions who have not received any chemotherapy are good candidates for peptide-based immunotherapy. Combining peptide vaccination and immune checkpoint inhibitors is an attractive option, and long-lived memory T cells are attracting attention. Memory T stem cells defined by CD95+ are long-lived and have the capacity for self-renewal and multidifferentiation. We also identified a novel memory T cell population, young memory T cells defined by CD73+CXCR3+. Regulation of such memory T stem cells will be useful for peptide vaccination and adoptive cell transfer.

    DOI: 10.1080/14712598.2016.1188075

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  • Identification of a novel human memory T-cell population with the characteristics of stem-like chemo-resistance. 国際誌

    Kenji Murata, Tomohide Tsukahara, Makoto Emori, Yuji Shibayama, Emi Mizushima, Hiroshi Matsumiya, Keiji Yamashita, Mitsunori Kaya, Yoshihiko Hirohashi, Takayuki Kanaseki, Terufumi Kubo, Tetsuo Himi, Shingo Ichimiya, Toshihiko Yamashita, Noriyuki Sato, Toshihiko Torigoe

    Oncoimmunology   5 ( 6 )   e1165376   2016年6月

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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)  

    High-dose chemotherapy may kill not only tumor cells but also immunocytes, and frequently induces severe lymphocytopenia. On the other hand, patients who recover from the nadir maintain immunity against infection, suggesting the existence of an unknown memory T-cell population with stress resistance, long-living capacity, proliferation and differentiation. Recently, the differentiation system of T-cell memory has been clarified using mouse models. However, the human T-cell memory system has great diversity induced by natural antigens derived from many pathogens and tumor cells throughout life, and profoundly differs from the mouse memory system constructed using artificial antigens and transgenic T cells. Here we report a novel human T-cell memory population, "young memory" T (TYM) cells. TYM cells are defined by positive expression of CD73, which represents high aldehyde dehydrogenase 1 (ALDH1) activity and CXCR3 among CD8(+)CD45RA(+)CD62L(+) T cells. TYM proliferate upon TCR stimulation, with differentiation capacity into TCM and TEM and drug resistance. Moreover, TYM are involved in memory function for viral and tumor-associated antigens in healthy donors and cancer patients, respectively. Regulation of TYM might be very attractive for peptide vaccination, adoptive cell-transfer therapy and hematopoietic stem cell transplantation.

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  • Cancer immunotherapy and immunological memory.

    Kenji Murata, Tomohide Tsukahara, Toshihiko Torigoe

    Nihon Rinsho Men'eki Gakkai kaishi = Japanese journal of clinical immunology   39 ( 1 )   18 - 22   2016年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    Human immunological memory is the key distinguishing hallmark of the adaptive immune system and plays an important role in the prevention of morbidity and the severity of infection. The differentiation system of T cell memory has been clarified using mouse models. However, the human T cell memory system has great diversity induced by natural antigens derived from many pathogens and tumor cells throughout life, and profoundly differs from the mouse memory system constructed using artificial antigens and transgenic T cells. We believe that only human studies can elucidate the human immune system. The importance of immunological memory in cancer immunotherapy has been pointed out, and the trafficking properties and long-lasting anti-tumor capacity of memory T cells play a crucial role in the control of malignant tumors. Adoptive cell transfer of less differentiated T cells has consistently demonstrated superior anti-tumor capacity relative to more differentiated T cells. Therefore, a human T cell population with the characteristics of stem cell memory is thought to be attractive for peptide vaccination and adoptive cell transfer. A novel human memory T cell population that we have identified is closer to the naive state than previous memory T cells in the T cell differentiation lineage, and has the characteristics of stem-like chemoresistance. Here we introduce this novel population and describe the fundamentals of immunological memory in cancer immunotherapy.

    DOI: 10.2177/jsci.39.18

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  • Prognostic impact of CD109 expression in myxofibrosarcoma. 国際誌

    Makoto Emori, Tomohide Tsukahara, Kenji Murata, Shintaro Sugita, Tomoko Sonoda, Mitsunori Kaya, Tamotsu Soma, Mikito Sasaki, Satoshi Nagoya, Tadashi Hasegawa, Takuro Wada, Noriyuki Sato, Toshihiko Yamashita

    Journal of surgical oncology   111 ( 8 )   975 - 9   2015年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: CD109, a TGF-β co-receptor, is reported to be preferentially expressed during the early stages of tumorigenesis in several carcinoma types. Myxofibrosarcoma is one of the most common soft-tissue sarcomas found in elderly patients. This study aimed to elucidate the impact of CD109 expression in myxofibrosarcoma on prognosis and recurrence. METHODS: Immunohistochemical staining for CD109 was performed on archival specimens from 37 patients. The Fisher exact test was used to evaluate association between CD109 expression and other clinicopathological features. Survival analysis was performed using Kaplan-Meier curves, and the prognostic significance was evaluated using the log-rank test. Multivariate analysis of factors was performed using Cox regression analysis. RESULTS: CD109 overexpression was significantly associated with surgical stage and distant metastasis (P = 0.00499, and 0.011, respectively). The frequency of CD109 overexpression was approximately 10% and CD109 overexpression was significantly associated with decreased overall survival (P = 0.004). Five-year overall survival rates 77% and 0% for CD109-negative and CD109-positive patients, respectively. In multivariate analysis, CD109 overexpression was the only independent risk factor for poor outcome (P = 0.02; hazard ratio, 10.64; 95% confidence interval, 1.47-76.91). CONCLUSIONS: Immunohistochemical CD109 expression in myxofibrosarcoma was associated with poor prognosis.

    DOI: 10.1002/jso.23934

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  • WS1-4 骨軟部肉腫に対するペプチドワクチン療法

    塚原 智英, 村田 憲治, 江森 誠人, 渡邉 一絵, 鳥越 俊彦

    日本臨床免疫学会会誌   38 ( 4 )   286b - 286b   2015年

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    記述言語:日本語   出版者・発行元:The Japan Society for Clinical Immunology  

    骨肉腫に代表される高悪性度骨軟部肉腫は予後不良であり,新しい治療法が求められている.我々は骨肉腫の免疫制御を目指し,自家の骨肉腫細胞株とCTLクローンを用いたcDNAライブラリ発現クローニングで世界で初めて骨肉腫抗原PBFを同定した.PBFは転写調節因子であり,骨肉腫のアポトーシスを制御している.PBF蛋白は骨肉腫組織の92%で,骨軟部肉腫全体では87%に発現が見られた.またPBF陽性の骨肉腫患者の予後は不良であり,PBFは予後不良骨肉腫の標的分子となり得る.そこで我々はHLA-A24/A2拘束性PBFペプチドを設計して骨肉腫患者のペプチド特異的CTL応答を解析し,まず骨肉腫患者に対するペプチドワクチン臨床試験を10例に行った.臨床効果は不変3例,増悪6例で,9例でペプチドに対する免疫応答が検出された.多発肺転移および皮下転移をもつ1例で,ペプチドワクチンに対する高い免疫応答がELISPOTで観察された.また局所再発巣に骨化とCD8陽性細胞浸潤を認めた.この症例はペプチドワクチン療法のみで加療され,合計31か月生存した.そして試験的に実施した再発粘液線維肉腫1例においてPBFペプチドに対する極めて高い免疫応答が誘導され,病勢にも相関した.これらの2症例はいずれも化学療法未施行例であり,病巣が小さかった(2 cm以下).これらの知見は今後のペプチドワクチン療法のさらなる実効化に大変重要と考えている

    その他リンク: http://search.jamas.or.jp/link/ui/2016051690

    DOI: 10.2177/jsci.38.286b

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  • Effect of cryotherapy after spine surgery. 国際誌

    Kenji Murata, Mitsunori Yoshimoto, Tsuneo Takebayashi, Kazunori Ida, Kazuhiko Nakano, Toshihiko Yamashita

    Asian spine journal   8 ( 6 )   753 - 8   2014年12月

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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)  

    STUDY DESIGN: Historical controlled trial. PURPOSE: To clarify the usefulness of cryotherapy after spine surgery. OVERVIEW OF LITERATURE: Cryotherapy has generally been performed subsequent to surgery on joints and in this application its clinical effects are well understood. However, cryotherapy has yet to be used following spine surgery. Its clinical efficacy in this context is unknown. METHODS: Thirty six patients had undergone one level microendoscopic surgery. Sixteen were enrolled into the cooling group, with the remaining 20 making up the no postoperative cryotherapy control group. Cryotherapy was performed at 5℃ using an icing system. A silicone balloon catheter with a thermo sensor on the tip was placed in the surgical wound. The temperature in the wound was recorded every 30 minutes until the next morning. The relationship between the depth of the sensor and the temperature in the wound were investigated using simple linear regression analysis. Laboratory data, visual analogue scale (VAS) for wound pain and postoperative bleeding were investigated. RESULTS: The mean temperature in the surgical wound was 37.0 in the control group and 35.0℃ in the cooling group (p<0.001). There was a positive correlation between the depth of the thermo sensor and the temperature in the wound in the cooling group (y=0.91x+30.2, r=0.67, p=0.004). There were no significant differences between the groups in terms of laboratory data, VAS or postoperative bleeding. CONCLUSIONS: The temperature in the wound was decreased significantly by spinal surgery cryotherapy.

    DOI: 10.4184/asj.2014.8.6.753

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  • Specific targeting of a naturally presented osteosarcoma antigen, papillomavirus binding factor peptide, using an artificial monoclonal antibody. 国際誌

    Tomohide Tsukahara, Makoto Emori, Kenji Murata, Takahisa Hirano, Norihiro Muroi, Masanori Kyono, Shingo Toji, Kazue Watanabe, Toshihiko Torigoe, Vitaly Kochin, Hiroko Asanuma, Hiroshi Matsumiya, Keiji Yamashita, Tetsuo Himi, Shingo Ichimiya, Takuro Wada, Toshihiko Yamashita, Tadashi Hasegawa, Noriyuki Sato

    The Journal of biological chemistry   289 ( 32 )   22035 - 47   2014年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Osteosarcoma is a rare but highly malignant tumor occurring most frequently in adolescents. The prognosis of non-responders to chemotherapy is still poor, and new treatment modalities are needed. To develop peptide-based immunotherapy, we previously identified autologous cytotoxic T lymphocyte-defined osteosarcoma antigen papillomavirus binding factor (PBF) in the context of HLA-B55 and the cytotoxic T lymphocyte epitope (PBF A2.2) presented by HLA-A2. PBF and HLA class I are expressed in ∼90 and 70% of various sarcomas, respectively. However, the expression status of peptide PBF A2.2 presented by HLA-A2 on osteosarcoma cells has remained unknown because it is difficult to generate a specific probe that reacts with the HLA·peptide complex. For detection and qualification of the HLA-A*02:01·PBF A2.2 peptide complex on osteosarcoma cells, we tried to isolate a single chain variable fragment (scFv) antibody directed to the HLA-*A0201·PBF A2.2 complex using a naïve scFv phage display library. As a result, scFv clone D12 with high affinity (KD = 1.53 × 10(-9) M) was isolated. D12 could react with PBF A2.2 peptide-pulsed T2 cells and HLA-A2+PBF+ osteosarcoma cell lines and simultaneously demonstrated that the HLA·peptide complex was expressed on osteosarcoma cells. In conclusion, scFv clone D12 might be useful to select candidate patients for PBF A2.2 peptide-based immunotherapy and develop antibody-based immunotherapy.

    DOI: 10.1074/jbc.M114.568725

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  • High expression of CD109 antigen regulates the phenotype of cancer stem-like cells/cancer-initiating cells in the novel epithelioid sarcoma cell line ESX and is related to poor prognosis of soft tissue sarcoma. 国際誌

    Makoto Emori, Tomohide Tsukahara, Masaki Murase, Masanobu Kano, Kenji Murata, Akari Takahashi, Terufumi Kubo, Hiroko Asanuma, Kazuyo Yasuda, Vitaly Kochin, Mitsunori Kaya, Satoshi Nagoya, Jun Nishio, Hiroshi Iwasaki, Tomoko Sonoda, Tadashi Hasegawa, Toshihiko Torigoe, Takuro Wada, Toshihiko Yamashita, Noriyuki Sato

    PloS one   8 ( 12 )   e84187   2013年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Epithelioid sarcoma (ES) is a relatively rare, highly malignant soft tissue sarcoma. The mainstay of treatment is resection or amputation. Currently other therapeutic options available for this disease are limited. Therefore, a novel therapeutic option needs to be developed. In the present study, we established a new human ES cell line (ESX) and analyzed the characteristics of its cancer stem-like cells/cancer-initiating cells (CSCs/CICs) based on ALDH1 activity. We demonstrated that a subpopulation of ESX cells with high ALDH1 activity (ALDH(high) cells) correlated with enhanced clonogenic ability, sphere-formation ability, and invasiveness in vitro and showed higher tumorigenicity in vivo. Next, using gene expression profiling, we identified CD109, a GPI-anchored protein upregulated in the ALDH(high) cells. CD109 mRNA was highly expressed in various sarcoma cell lines, but weakly expressed in normal adult tissues. CD109-positive cells in ESX predominantly formed spheres in culture, whereas siCD109 reduced ALDH1 expression and inhibited the cell proliferation in vitro. Subsequently, we evaluated the expression of CD109 protein in 80 clinical specimens of soft tissue sarcoma. We found a strong correlation between CD109 protein expression and the prognosis (P = 0.009). In conclusion, CD109 might be a CSC/CIC marker in epithelioid sarcoma. Moreover, CD109 is a promising prognostic biomarker and a molecular target of cancer therapy for sarcomas including ES.

    DOI: 10.1371/journal.pone.0084187

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  • Union rates and prognostic variables of osteoporotic vertebral fractures treated with a rigid external support. 国際誌

    Kenji Murata, Goichi Watanabe, Satoshi Kawaguchi, Kohei Kanaya, Keiko Horigome, Hideki Yajima, Tomonori Morita, Toshihiko Yamashita

    Journal of neurosurgery. Spine   17 ( 5 )   469 - 75   2012年11月

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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)  

    OBJECT: External supports serve as a traditional treatment option for osteoporotic vertebral fractures (OVFs). However, the role of external supports in the treatment of OVF remains inconclusive. The purpose of this study was to determine the role of a rigid external support in the healing of OVFs by prospectively evaluating union (fracture settling) rates and prognostic variables for patients suffering from an incident OVF. METHODS: Fifty-five patients with acute back pain were enrolled in this study after being diagnosed with an OVF based on MRI findings. Patients were treated using a plastic thoracolumbosacral orthosis (TLSO) and underwent follow-up at 2, 3, and 6 months. Vertebrae were referred to as "settled" when there was no dynamic mobility on sitting lateral and supine lateral radiographs. At the time of the 3- and 6-month follow-up visits, the patients were divided into 2 groups, the "settled group" and the "unsettled group." Patients in these groups were compared with regard to clinical and radiographic features. RESULTS: Of the 55 patients enrolled, 53 patients were followed up for 6 months. There were 14 men and 39 women with an average age of 75.3 years. Fracture settling of the affected vertebra was defined in 54.7% of the patients at 2 months, in 79.2% at 3 months, and in 88.7% at 6 months. All 5 components of the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire improved significantly both at 3 months and 6 months. Patients in the unsettled group exhibited a statistically greater likelihood of having fractures at the thoracolumbar junction, Type A3 fractures, and fractures with a diffuse low-intensity area on T2-weighted MRI studies at 3 months. In contrast, at 6 months, the only statistically significant difference between the groups was patient age. CONCLUSIONS: The biomechanical disadvantages of OVFs (location, type, and size) adversely influencing the fracture healing were overcome by the treatment using a TLSO within 6 months. The authors' findings show that a TLSO plays a biomechanical role in the healing of OVFs.

    DOI: 10.3171/2012.7.SPINE122

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  • Replantation of severed foot at the metatarsophalangeal joint: a case report. 国際誌

    Kohei Kanaya, Takuro Wada, Kenji Murata, Toshihiko Yamashita

    Microsurgery   32 ( 5 )   415 - 7   2012年7月

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    記述言語:英語  

    DOI: 10.1002/micr.21968

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書籍等出版物

  • 次世代CAR-T細胞

    村田 憲治, 平野 直人( 担当: 分担執筆 範囲: TCR-T細胞療法の現状と期待:適応拡大と有効性向上のための新技術)

    羊土社  2023年11月  ( ISBN:9784758125734

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    総ページ数:p2948-3074   記述言語:日本語  

    CiNii Books

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MISC

  • 末端黒子型黒色腫における腫瘍浸潤リンパ球の単細胞免疫プロファイリング

    箕輪智幸, 箕輪智幸, 村田憲治, 廣橋良彦, 宇原久, 鳥越俊彦

    日本病理学会会誌   112 ( 1 )   2023年

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  • プラチナ製剤耐性がん細胞を標的とする抗HLA-A2/Claspinペプチド特異的人工抗体の開発

    水江由佳, 廣橋良彦, 塚原智英, 金関貴幸, 久保輝文, 村田憲治, 鳥越俊彦

    日本病理学会会誌   112 ( 1 )   2023年

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  • マクロファージとメラノーマのハイブリッド細胞は免疫回避する

    箕輪智幸, 廣橋良彦, 村田憲治, 久保輝文, 鳥越俊彦

    日本病理学会会誌   111 ( 1 )   2022年

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  • 次世代がん免疫療法に向けた免疫病理学研究

    鳥越俊彦, 廣橋良彦, 塚原智英, 金関貴幸, 久保輝文, 村田憲治

    日本病理学会会誌   111 ( 2 )   2022年

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  • dMMR大腸がん組織プロテオゲノミクス解析によるHLAクラスIネオアンチゲン同定と反応TCR解析

    時田芹奈, 時田芹奈, 金関貴幸, 村田憲治, 中津川宗秀, 平間知美, 平間知美, 佐藤昇志, 佐藤昇志, 秦史壯, 鳥越俊彦

    日本病理学会会誌   111 ( 1 )   2022年

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  • シングルセル免疫プロファイリングによる末端黒子型黒色腫の腫瘍浸潤リンパ球の解析

    箕輪智幸, 村田憲治, 村田憲治, 廣橋良彦, 宇原久, 鳥越俊彦

    日本癌学会学術総会抄録集(Web)   81st   2022年

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  • Proteogenomic approachによるT細胞の標的HLAリガンドのランドスケープ

    鳥越俊彦, 廣橋良彦, 塚原智英, 塚原智英, 金関貴幸, 久保輝文, 村田憲治, 村田憲治, 中津川宗秀

    日本癌学会学術総会抄録集(Web)   81st   2022年

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  • 腫瘍微小環境における免疫抵抗性機序の解明

    廣橋良彦, 久保輝文, 村田憲治, 金関貴幸, 塚原智英, 鳥越俊彦

    日本病理学会会誌   111 ( 1 )   2022年

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産業財産権

  • T細胞受容体及びその使用方法

    平野 直人, 村田 憲治, 佐相 薫葉子

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    出願人:ユニバーシティー ヘルス ネットワーク

    出願番号:特願2025-011527  出願日:2025年1月

    公開番号:特開2025-063321  公開日:2025年4月

    J-GLOBAL

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  • T細胞受容体及びその使用方法

    平野 直人, 村田 憲治, 佐相 薫葉子

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    出願人:ユニバーシティー ヘルス ネットワーク

    出願番号:特願2025-006913  出願日:2025年1月

    公開番号:特開2025-062611  公開日:2025年4月

    J-GLOBAL

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  • T細胞受容体及びその使用方法

    平野 直人, 村田 憲治, 佐相 薫葉子

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    出願人:ユニバーシティー ヘルス ネットワーク

    出願番号:特願2024-163997  出願日:2024年9月

    公開番号:特開2025-000725  公開日:2025年1月

    J-GLOBAL

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  • ペプチド-HLA複合体およびその産生方法

    平野 直人, 中津川 宗秀, ラフマン ムハンメッド アアシク, 村田 憲治

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    出願人:ユニバーシティー ヘルス ネットワーク

    出願番号:特願2022-093279  出願日:2022年6月

    公開番号:特開2022-137028  公開日:2022年9月

    J-GLOBAL

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  • T細胞受容体及びその使用方法

    平野 直人, 村田 憲治, 佐相 薫葉子

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    出願人:ユニバーシティー ヘルス ネットワーク

    出願番号:特願2021-557228  出願日:2020年3月

    公表番号:特表2022-527267  公表日:2022年6月

    J-GLOBAL

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  • T細胞受容体及びその使用方法

    平野 直人, 村田 憲治, 佐相 薫葉子

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    出願人:ユニバーシティー ヘルス ネットワーク

    出願番号:IB2020051813  出願日:2020年3月

    特許番号/登録番号:特許第7576037号  登録日:2024年10月 

    J-GLOBAL

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  • T細胞受容体及びその使用方法

    平野 直人, 村田 憲治, 佐相 薫葉子

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    出願人:ユニバーシティー ヘルス ネットワーク

    出願番号:IB2020051808  出願日:2020年3月

    特許番号/登録番号:特許第7561133号  登録日:2024年9月 

    J-GLOBAL

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受賞

  • 学術奨励賞

    2018年   北海道整形災害外科学会  

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共同研究・競争的資金等の研究課題

  • cDNAディスプレイペプチドライブラリー搭載改変HLAを用いた骨軟部肉腫抗原探索

    研究課題/領域番号:25K12531  2025年4月 - 2028年3月

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    村田 憲治

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    担当区分:研究代表者 

    配分額:4550000円 ( 直接経費:3500000円 、 間接経費:1050000円 )

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  • 網羅的肉腫抗原解析を可能とするペプチド/HLA複合体単離システムの開発

    研究課題/領域番号:23K15720  2023年4月 - 2025年3月

    日本学術振興会  科学研究費助成事業  若手研究

    村田 憲治

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    担当区分:研究代表者 

    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    骨軟部肉腫疾患(以下、肉腫)に対する既存の免疫療法の奏効率はいまだ低く、効果的ながん免疫療法を行うためには、治療標的として有効な肉腫抗原と抗腫瘍効果の高いエフェクター細胞が必要である。悪性黒色腫患者に対する腫瘍浸潤Tリンパ球(TIL)を用いた養子免疫療法(TIL療法)は、持続的な臨床効果をもたらすことが報告されている。そして、悪性黒色腫のTILから単離されたTCRがすべて腫瘍に反応することを示されている。軟部肉腫に含まれるTILが腫瘍反応性であることも示されており、悪性黒色腫と同様に肉腫TIL由来のTCRも肉腫抗原に対して反応を示す可能性が高い。
    本研究では、効果的な免疫療法の開発に向けて、新たに考案したペプチド/HLA単離システムを用いて肉腫浸潤Tリンパ球由来のTCRが反応する新規肉腫抗原を同定することである。
    骨肉腫の切除検体からTILを分離して単細胞レベルでのTCRレパトアと遺伝子発現解析を行なった。CD8陽性で、PD-1や4-1BBを発現しているTCRレパトアが存在し、腫瘍を認識している可能性が高いT細胞集団であった。複数のTCRを選択し、TCR遺伝子導入T細胞(TCR-T細胞)を各々作成した。自家腫瘍細胞株を樹立できなかったため、他科家細胞株に患者HLAを単一発現させ、標的細胞を作成した。TCR-T細胞と共培養して免疫応答を確認し、陽性反応の検出を試みている。また、抗原同定の新技術開発も進めている。

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  • 腫瘍反応性TCRをプローブとして用いた新たな肉腫抗原同定法の開発

    研究課題/領域番号:22ama221308h0001  2022年 - 2023年

    日本医療研究開発機構(AMED) 次世代がん医療加速化研究事業(P-PROMOTE)

    村田 憲治

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  • 抗肉腫ヒト人工T細胞療法に向けたTCR・抗原ペア網羅的解析プラットフォーム開発

    研究課題/領域番号:21K16659  2021年4月 - 2023年3月

    日本学術振興会  科学研究費助成事業  若手研究

    村田 憲治

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    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    骨軟部肉腫は若年者に多く発生する悪性度の高い希少がんであり、化学療法に反応しない進行期肉腫患者の予後は不良である。近年、「がん免疫療法」は飛躍的に進化し、手術療法、抗がん剤治療、放射線治療の3大治療に次ぐ第4の治療法として注目をされており、ステージ 4 のがん患者でも劇的回復を示す症例がみられる。肉腫に対しては、がん精巣抗原の一つである NY-ESO-1 を標的として、T 細胞受容体(TCR)遺伝子を導入した T 細胞(TCR-T 細胞)を用いた T 細胞輸注療法が末期滑膜肉腫の 50%以 上に部分効果を示すことも報告されている。しかしながら、他の難治性肉腫疾患に対する既存の免疫療法の奏効率はいまだ低く、さらに肉腫に発現する特異抗原とそれを認識するTCR遺伝子の報告は少ない。
    本研究の目的は、骨軟部肉腫に対する効果的な遺伝子改変T細胞療法の実行化に向けて、肉腫浸潤Tリンパ球(TIL)由来の肉腫反応性TCRが認識する抗原を同定するための新たな解析プラットフォームを開発することである。
    平滑筋肉腫2症例(LMS02、LMS07)の切除検体からTILを分離して10x Genomics社のChromium Controllerを用いて単細胞レベルでのTCRレパトアと遺伝子発現解析を行なった。いずれもTCRのクローナリティが高いT細胞が存在し、さらにそれらは活性化マーカーや疲弊マーカーの発現がやや高く、腫瘍を認識している可能性が高い細胞集団であった。CD8陽性で、PD-1陽性かつ4-1BB陽性のTCRをサブクローニングし、TCR-T細胞を作成した。このTCRを抗原探索のプローブとして用い、新たな肉腫抗原を同定する。

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  • シングルセル解析による肉腫浸潤Tリンパ球応答の解明

    研究課題/領域番号:20K22980  2020年9月 - 2022年3月

    日本学術振興会  科学研究費助成事業  研究活動スタート支援

    村田 憲治

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    配分額:2860000円 ( 直接経費:2200000円 、 間接経費:660000円 )

    粘液炎症性線維芽細胞肉腫の切除片から腫瘍浸潤リンパ球(TIL)を分離し、シングルセル解析を行った。TILの分画はCD8陽性T細胞優位で、上位2つのT細胞受容体(TCR)が40%以上を占めていた。これらを含めたTCRクローナリティーの高いTILは、メモリーマーカーの発現が見られず、一方で疲弊マーカーや活性化マーカー、サイトカイン遺伝子の発現が高い傾向にあり、腫瘍を認識する可能性が高いと考えられた。

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