Updated on 2024/06/22

写真a

 
Ishino Takamasa
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Special-Appointment Assistant Professor
Position
Special-Appointment Assistant Professor
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Degree

  • 医学博士 ( 2024.3   千葉大学 )

  • 学士(医学) ( 2016.3   千葉大学 )

Research Interests

  • 消化器内科

  • 腫瘍免疫

  • 内科

  • 腫瘍微小環境

Research Areas

  • Life Science / Immunology

  • Life Science / Hematology and medical oncology

  • Life Science / Gastroenterology

  • Life Science / General internal medicine

Education

  • 千葉大学医学薬学府(卓越大学院プログラム)    

    2020.4 - 2024.3

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  • Chiba University   医学部  

    2010.4 - 2016.3

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Research History

  • Okayama University   Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences   Assistant Professor

    2024.4

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  • 千葉大学医学部   特任研究員

    2021.7 - 2024.3

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  • 千葉大学医学部附属病院 消化器内科 医員

    2020.4 - 2021.7

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  • 沼津市立病院 消化器内科 医員

    2019.4 - 2020.3

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  • 千葉市立青葉病院 内科 医員

    2018.4 - 2019.3

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  • 横浜労災病院 初期臨床研修医

    2016.4 - 2018.3

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Professional Memberships

 

Papers

  • Abstract 7536: CD4+T cell exhaustion in the tumor microenvironment and antitumor immunity

    Joji Nagasaki, Wenhao Zhou, Shusuke Kawashima, Takamasa Ishino, Katsushige Kawase, Youki Ueda, Kazuo Yamashita, Tomofumi Watanabe, Takashi Inozume, Yosuke Togashi

    Cancer Research   84 ( 6_Supplement )   7536 - 7536   2024.3

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

    Abstract

    Background: Immune checkpoint inhibitors (ICIs) exert clinical efficacy against various types of cancer through reinvigoration of exhausted CD8+ T cells that attack cancer cells directly in the tumor microenvironment (TME). However, compared to CD8+ T cell exhaustion, the role of CD4+ T cell exhaustion in antitumor immunity remains unclear.

    Methods and Results: From single-cell sequencing for tumor-infiltrating lymphocytes (TILs) from patients with melanoma and mouse models, we found that CXCL13, which is highly expressed in tumor-infiltrating exhausted CD8+ T cells, induces PD-1+CXCR5+CD4+ follicular helper T (TFH)-like cell infiltration, which could contribute to antitumor immunity. Furthermore, a part of the TFH-like cells in the TME exhibits cytotoxicity and directly attacks MHC-II-expressing tumors. RNA velocity and latent time analysis in single-cell sequencing for melanoma TILs showed that the differentiation of TFH-like cells from the naive CD4+ T cells were different from that of other CD4+ T cells. In addition, the TFH-like cytotoxic CD4+ T cells were at the late stage of differentiation and some non-cytotoxic TFH-like cells might differentiate into TFH-like cytotoxic CD4+ T cells. We additionally found considerable overlapped clonotypes between the cytotoxic and non-cytotoxic clusters. TFH-like cytotoxic CD4+ T cells have high LAG-3/BLIMP1 and low TCF1 expression without self-renewal ability, whereas non-cytotoxic TFH-like cells express low LAG-3/BLIMP1 and high TCF1 with self-renewal ability, closely resembling the relationship between terminally differentiated and stem-like progenitor exhaustion in CD8+ T cells, respectively.

    Conclusion: Our findings provide novel insights into TFH-like CD4+ T cell exhaustion with helper progenitor and cytotoxic differentiated functions, which mediates antitumor immunity orchestrally with CD8+ T cells.

    Citation Format: Joji Nagasaki, Wenhao Zhou, Shusuke Kawashima, Takamasa Ishino, Katsushige Kawase, Youki Ueda, Kazuo Yamashita, Tomofumi Watanabe, Takashi Inozume, Yosuke Togashi. CD4+T cell exhaustion in the tumor microenvironment and antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7536.

    DOI: 10.1158/1538-7445.am2024-7536

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  • Stem-like progenitor and terminally differentiated TFH-like CD4+ T cell exhaustion in the tumor microenvironment. Reviewed International journal

    Wenhao Zhou, Shusuke Kawashima, Takamasa Ishino, Katsushige Kawase, Youki Ueda, Kazuo Yamashita, Tomofumi Watanabe, Masahito Kawazu, Hiromichi Dansako, Yutaka Suzuki, Hiroyoshi Nishikawa, Takashi Inozume, Joji Nagasaki, Yosuke Togashi

    Cell reports   43 ( 2 )   113797 - 113797   2024.2

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    Immune checkpoint inhibitors exert clinical efficacy against various types of cancer through reinvigoration of exhausted CD8+ T cells that attack cancer cells directly in the tumor microenvironment (TME). Using single-cell sequencing and mouse models, we show that CXCL13, highly expressed in tumor-infiltrating exhausted CD8+ T cells, induces CD4+ follicular helper T (TFH) cell infiltration, contributing to anti-tumor immunity. Furthermore, a part of the TFH cells in the TME exhibits cytotoxicity and directly attacks major histocompatibility complex-II-expressing tumors. TFH-like cytotoxic CD4+ T cells have high LAG-3/BLIMP1 and low TCF1 expression without self-renewal ability, whereas non-cytotoxic TFH cells express low LAG-3/BLIMP1 and high TCF1 with self-renewal ability, closely resembling the relationship between terminally differentiated and stem-like progenitor exhaustion in CD8+ T cells, respectively. Our findings provide deep insights into TFH-like CD4+ T cell exhaustion with helper progenitor and cytotoxic differentiated functions, mediating anti-tumor immunity orchestrally with CD8+ T cells.

    DOI: 10.1016/j.celrep.2024.113797

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  • Treg細胞の活性化CTLA-4非依存性免疫抑制によるCTLA-4遮断の不安定な抗腫瘍効果(Disturbed anti-tumor effect of CTLA-4 blockade by activated CTLA-4-independent immunosuppression of Treg cells)

    渡部 智文, 石野 貴雅, 上田 優輝, 長崎 譲慈, 河田 達志, 定平 卓也, 岩田 健宏, 片山 聡, 枝村 康平, 小林 泰之, 團迫 浩方, 荒木 元朗, 冨樫 庸介

    西日本泌尿器科学会総会抄録集   75回   185 - 185   2023.11

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  • CTLA-4の単純な阻害はTreg細胞のCTLA-4以外の免疫抑制機構の活性化を引き起こす(Anti-tumor effects of CTLA-4 blockade are distrubed by activated CTLA-4-independent immunosuppression of Treg cells)

    渡部 智文, 石野 貴雅, 上田 優輝, 長崎 譲慈, 丸山 雄樹, 河田 達志, 定平 卓也, 岩田 健宏, 片山 聡, 西村 慎吾, 枝村 康平, 小林 知子, 小林 泰之, 團迫 浩方, 荒木 元朗, 冨樫 庸介

    日本癌学会総会記事   82回   1380 - 1380   2023.9

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  • CTLA-4の単純な阻害はTreg細胞のCTLA-4以外の免疫抑制機構の活性化を引き起こす(Anti-tumor effects of CTLA-4 blockade are distrubed by activated CTLA-4-independent immunosuppression of Treg cells)

    渡部 智文, 石野 貴雅, 上田 優輝, 長崎 譲慈, 丸山 雄樹, 河田 達志, 定平 卓也, 岩田 健宏, 片山 聡, 西村 慎吾, 枝村 康平, 小林 知子, 小林 泰之, 團迫 浩方, 荒木 元朗, 冨樫 庸介

    日本癌学会総会記事   82回   1380 - 1380   2023.9

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  • Potential of circulating receptor-interacting protein kinase 3 levels as a marker of acute liver injury. Reviewed International journal

    Takayuki Kondo, Kentaro Fujimoto, Kisako Fujiwara, Sae Yumita, Takamasa Ishino, Keita Ogawa, Miyuki Nakagawa, Terunao Iwanaga, Keisuke Koroki, Hiroaki Kanzaki, Masanori Inoue, Kazufumi Kobayashi, Soichiro Kiyono, Masato Nakamura, Naoya Kanogawa, Sadahisa Ogasawara, Shingo Nakamoto, Tetsuhiro Chiba, Jun Kato, Keiichi Fujiwara, Naoya Kato

    Scientific reports   13 ( 1 )   14043 - 14043   2023.8

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    The pathogenesis of acute liver failure (ALF) involves cell death. Necroptosis is a newly suggested programmed cell death, and receptor-interacting protein kinase 3 (RIPK3) has been reported as a marker for necroptosis. However, there are few reports on necroptosis in ALF. Therefore, we evaluated the role of cell death markers such as cytokeratin (CK) 18, cleaved CK (cCK) 18, and RIPK3 in ALF, as well as cytokines and hepatocyte growth factor (HGF). Seventy-one hospitalized patients with acute liver injury (38 nonsevere hepatitis [non-SH]/22 severe hepatitis [SH]/11 ALF) were studied. No significant difference was found for cytokines, but a substantial increase in HGF levels was found following the severity of hepatitis. The non-SH group had lower levels of CK18 and cCK18 than the SH/ALF group. RIPK3 was significantly lower in the non-SH/SH group than in the ALF group. HGF, RIPK3, and albumin levels were found to be important predictive variables. The present study suggests that cCK18, CK18, and RIPK3 are associated with the severity of hepatitis. RIPK3 and other markers related cell death may be useful for understanding the pathogenesis of ALF and as a prognostic marker of acute liver injury.

    DOI: 10.1038/s41598-023-41425-6

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  • Low frequency of intracranial progression in advanced NSCLC patients treated with cancer immunotherapies. Reviewed International journal

    Naoya Kemmotsu, Kiichiro Ninomiya, Kei Kunimasa, Takamasa Ishino, Joji Nagasaki, Yoshihiro Otani, Hiroyuki Michiue, Eiki Ichihara, Kadoaki Ohashi, Takako Inoue, Motohiro Tamiya, Kazuko Sakai, Youki Ueda, Hiromichi Dansako, Kazuto Nishio, Katsuyuki Kiura, Isao Date, Yosuke Togashi

    International journal of cancer   2023.8

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    Intracranial metastases are common in nonsmall-cell lung cancer (NSCLC) patients, whose prognosis is very poor. In addition, intracranial progression is common during systemic treatments due to the inability to penetrate central nervous system (CNS) barriers, whereas the intracranial effects of cancer immunotherapies remain unclear. We analyzed clinical data to evaluate the frequency of intracranial progression in advanced NSCLC patients treated with PD-1 blockade therapies compared with those treated without PD-1 blockade therapies, and found that the frequency of intracranial progression in advanced NSCLC patients treated with PD-1 blockade therapies was significantly lower than that in patients treated with cytotoxic chemotherapies. In murine models, intracranial rechallenged tumors after initial rejection by PD-1 blockade were suppressed. Accordingly, long-lived memory precursor effector T cells and antigen-specific T cells were increased by PD-1 blockade in intracranial lesions. However, intracranial rechallenged different tumors are not suppressed. Our results indicate that cancer immunotherapies can prevent intracranial progression, maintaining long-term effects intracranially as well as systemically. If intracranial recurrence occurs during the treatment with PD-1 blockade therapies, aggressive local therapies could be worthwhile.

    DOI: 10.1002/ijc.34700

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  • Cabozantinib for Advanced Hepatocellular Carcinoma in the Latest Real-World Practice: A Multicenter Retrospective Analysis. Reviewed International journal

    Hiroaki Kanzaki, Sadahisa Ogasawara, Tomomi Okubo, Norio Itokawa, Ryohei Yoshino, Kentaro Fujimoto, Tadayoshi Kogure, Sae Yumita, Takamasa Ishino, Keita Ogawa, Terunao Iwanaga, Miyuki Nakagawa, Kisako Fujiwara, Ryuta Kojima, Keisuke Koroki, Masanori Inoue, Kazufumi Kobayashi, Naoya Kanogawa, Soichiro Kiyono, Masato Nakamura, Takayuki Kondo, Ryo Nakagawa, Shingo Nakamoto, Ryosuke Muroyama, Ei Itobayashi, Masanori Atsukawa, Jun Kato, Naoya Kato

    Drugs - real world outcomes   2023.7

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    BACKGROUND: Cabozantinib was found to be effective as a second- or third-line treatment after sorafenib in patients with advanced hepatocellular carcinoma (HCC) in the phase 3 CELESTIAL trial. So far, as immunotherapy has substituted molecular target agents as the primary systemic therapy for advanced HCC, cabozantinib is extensively used in the latest real-world clinical practice in a greatly different position than that shown by the CELESTIAL trial. In the current analysis, we examined the safety and effectiveness of cabozantinib administration in real-life settings for patients with advanced HCC. METHODS: We retrospectively obtained data from patients with advanced HCC who received cabozantinib in three institutions in Japan between 14 September 2018 and 30 November 2021. RESULTS: During the study period, 23 patients with advanced HCC received cabozantinib. Our cohort included 21.7% of patients with Child-Pugh class B, and 52.2% of patients in fourth line or later. The median progression-free survival of patients given cabozantinib was 3.7 months. Regarding patients with Child-Pugh class B or administration in fourth line or later, the discontinuation rate due to adverse events in patients who initialized at 40 or 20 mg was lower than those who initialized at 60 mg (42.9% versus 75.0%). Patients who were able to continue treatment with cabozantinib for more than 3 months were more likely to undergo dose reduction than those who did not (85.7% versus 25.0%). CONCLUSIONS: Cabozantinib has recently been administered to a diverse range of patients, including those who were not enrolled in the CELESTIAL trial. Deliberate dose reduction could potentially offer clinical benefits to patients with impaired liver function. Furthermore, managing adverse events by reducing the dose could play a crucial role in extending the duration of treatment with cabozantinib. The preprint version of this work is available on https://www.researchsquare.com/article/rs-2655181/v1 .

    DOI: 10.1007/s40801-023-00379-x

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  • Estimation of the effect of atezolizumab plus bevacizumab on pulmonary arterial hypertension using computed tomography in HCC patients. Reviewed International journal

    Takayuki Kondo, Kisako Fujiwara, Miyuki Nakagawa, Kentaro Fujimoto, Sae Yumita, Takamasa Ishino, Keita Ogawa, Terunao Iwanaga, Keisuke Koroki, Hiroaki Kanzaki, Masanori Inoue, Kazufumi Kobayashi, Soichiro Kiyono, Masato Nakamura, Naoya Kanogawa, Sadahisa Ogasawara, Shingo Nakamoto, Tetsuhiro Chiba, Jun Kato, Naoya Kato

    Scientific reports   13 ( 1 )   11524 - 11524   2023.7

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    The effect of the combination of atezolizumab and bevacizumab (Atez/Bev) for hepatocellular carcinoma (HCC) on pulmonary arterial hypertension (PAH) is unknown. Estimation of PAH by using computed tomography (CT) has recently been proposed. Thus, we aimed to estimate the effect of Atez/Bev on PAH using CT. Altogether, 113 patients who received Atez/Bev for HCC were enrolled. Probable PAH was defined as the diameter of the main pulmonary artery (mPA-D) ≥ 33 mm, whereas suspicious PAH was defined as mPA-D ≥ 29 mm or mPA-D/the diameter of the ascending aorta (aAo-D) ≥ 1.0. Before treatment, probable/suspicious PAH were diagnosed in 7 (6.7%)/22 (21.0%) patients, respectively. mPA-D and mPA-D/aAo-D significantly increased after induction of Atez/Bev. The increment of mPA-D was correlated with the occurrence of post-treatment respiratory/heart failure. In analysis of 55 patients who underwent CT at 3 months after the last dose of Atez/Bev, mPA-D and mPA-D/aAo-D significantly decreased. However, in the group with continuous treatment of other molecular-targeted drugs after Atez/Bev, mPA-D and mPA-D/aAo-D showed no significant change. In conclusion, PAH may not be a rare complication in patients with HCC and should be managed carefully because of the possible negative effect of Atez/Bev on PAH.

    DOI: 10.1038/s41598-023-38377-2

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  • 薬物療法全盛時代における進行肝細胞癌に対する動注化学療法のリポジショニング

    渡部 主樹, 小林 和史, 小笠原 定久, 藤本 健太郎, 石野 貴雅, 小川 慶太, 弓田 冴, 岩永 光巨, 中川 美由貴, 藤原 希彩子, 神崎 洋彰, 興梠 慧輔, 井上 将法, 中村 昌人, 叶川 直哉, 清野 宗一郎, 近藤 孝行, 中本 晋吾, 千葉 哲博, 加藤 直也

    肝臓   64 ( Suppl.1 )   A465 - A465   2023.4

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  • Hyperprogressive disease during atezolizumab plus bevacizumab treatment in patients with advanced hepatocellular carcinoma from Japanese real-world practice. Reviewed International journal

    Sae Yumita, Sadahisa Ogasawara, Miyuki Nakagawa, Susumu Maruta, Tomomi Okubo, Norio Itokawa, Yotaro Iino, Masamichi Obu, Yuki Haga, Atsuyoshi Seki, Tadayoshi Kogure, Takamasa Ishino, Keita Ogawa, Kisako Fujiwara, Terunao Iwanaga, Naoto Fujita, Takafumi Sakuma, Ryuta Kojima, Hiroaki Kanzaki, Keisuke Koroki, Masanori Inoue, Kazufumi Kobayashi, Soichiro Kiyono, Masato Nakamura, Naoya Kanogawa, Tomoko Saito, Takayuki Kondo, Ryo Nakagawa, Shingo Nakamoto, Ryosuke Muroyama, Tetsuhiro Chiba, Ei Itobayashi, Masanori Atsukawa, Yoshihiro Koma, Ryosaku Azemoto, Kenji Ito, Hideaki Mizumoto, Jun Kato, Naoya Kato

    BMC gastroenterology   23 ( 1 )   101 - 101   2023.3

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    BACKGROUND: Hyperprogressive disease (HPD) is a phenomenon with greatly accelerated tumor growth and clinical deterioration rates compared to pre-therapy, in patients treated with immune checkpoint inhibitors (ICI). The aim of this study is to clarify the reality of HPD in patients with advanced hepatocellular carcinoma (HCC) who were treated with atezolizumab plus bevacizumab (Atez/Bev) using tumor dynamics. METHODS: Medical records of consecutive patients with advanced HCC who were treated with Atez/Bev were retrospectively reviewed. HPD was defined as a more than two- or fourfold increase in tumor growth rate (TGR) or tumor growth kinetics rate (TGKR) before and after treatment. Overall survival (OS) and baseline characteristics with or without HPD were analyzed. RESULTS: A total of 85 patients were included in the analysis. When HPD was defined as a twofold of TGR or TGKR, 8 patients (8/85, 9.4%) had HPD and 11 had PD without HPD. A total of 5 patients (5/85, 5.9%) were diagnosed with HPD and 14 with PD without HPD when HPD was defined as a fourfold of TGR or TGKR. No significant difference was observed in the baseline characteristics between HPD and non-HPD. CONCLUSION: The prevalence of HPD in patients with advanced HCC treated with Atez/Bev was lower than those treated with nivolumab monotherapy. The HPD mechanism in ICI combined with antibodies targeting vascular endothelial growth factor (VEGF) remains to be elucidated.

    DOI: 10.1186/s12876-023-02731-5

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  • Use of ramucirumab for various treatment lines in real-world practice of patients with advanced hepatocellular carcinoma. Reviewed International journal

    Naoya Kanogawa, Sadahisa Ogasawara, Susumu Maruta, Yotaro Iino, Masamichi Obu, Takamasa Ishino, Keita Ogawa, Sae Yumita, Terunao Iwanaga, Hidemi Unozawa, Miyuki Nakagawa, Kisako Fujiwara, Takafumi Sakuma, Naoto Fujita, Ryuta Kojima, Hiroaki Kanzaki, Keisuke Koroki, Kazufumi Kobayashi, Masanori Inoue, Soichiro Kiyono, Masato Nakamura, Takayuki Kondo, Tomoko Saito, Ryo Nakagawa, Shingo Nakamoto, Ryosuke Muroyama, Tetsuhiro Chiba, Ei Itobayashi, Yoshihiro Koma, Ryosaku Azemoto, Jun Kato, Naoya Kato

    BMC gastroenterology   23 ( 1 )   70 - 70   2023.3

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    PURPOSE: Ramucirumab was shown to be effective as a second-line treatment after sorafenib in patients with advanced hepatocellular carcinoma (HCC) with alpha-fetoprotein levels > 400 ng/mL in a worldwide phase 3 trial. Ramucirumab is used in patients pretreated with various systemic therapies in clinical practice. We retrospectively examined the treatment outcomes of ramucirumab administered to advanced HCC patients after diverse systemic therapies. METHODS: Data were collected from patients with advanced HCC who received ramucirumab at three institutions in Japan. Radiological assessments were determined according to both Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and modified RECIST and the Common Terminology Criteria for Adverse Events version 5.0 was used to assess adverse events. RESULTS: A total of 37 patients treated with ramucirumab between June 2019 and March 2021 were included in the study. Ramucirumab was administered as second, third, fourth, and fifth-line treatment in 13 (35.1%), 14 (37.8%), eight (21.6%), and two (5.4%) patients, respectively. Most patients (29.7%) who received ramucirumab as a second-line therapy were pretreated with lenvatinib. We found grade 3 or higher adverse events only in seven patients and no significant changes in the albumin-bilirubin score during ramucirumab treatment in the present cohort. The median progression-free survival of patients treated with ramucirumab was 2.7 months (95% confidence interval, 1.6-7.3). CONCLUSION: Although ramucirumab is used for various lines of treatment other than second-line immediately after sorafenib, its safety and effectiveness were not significantly different from the findings of the REACH-2 trial.

    DOI: 10.1186/s12876-023-02674-x

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  • ナルメフェン投与の単一内科での投与成績と今後の課題

    清野 宗一郎, 小暮 禎祥, 藤本 健太郎, 弓田 冴, 石野 貴雅, 小川 慶太, 藤原 希彩子, 中川 美由貴, 岩永 光巨, 興梠 慧輔, 神崎 洋彰, 小林 和史, 井上 将法, 中村 昌人, 叶川 直哉, 近藤 孝行, 小笠原 定久, 中本 晋吾, 千葉 哲博, 加藤 直也

    日本消化器病学会雑誌   120 ( 臨増総会 )   A400 - A400   2023.3

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  • Successful Identification of a Novel Therapeutic Compound for Hepatocellular Carcinoma Through Screening of ADAM9 Inhibitors. Reviewed International journal

    Keita Ogawa, Tetsuhiro Chiba, Masato Nakamura, Jun Arai, Jiaqi Zhang, Yaojia Ma, N A Qiang, Junjie Ao, Sae Yumita, Takamasa Ishino, Motoyasu Kan, Terunao Iwanaga, Miyuki Nakagawa, Kisako Fujiwara, Takafumi Sakuma, Hiroaki Kanzaki, Keisuke Koroki, Yuko Kusakabe, Kazufumi Kobayashi, Naoya Kanogawa, Soichiro Kiyono, Takayuki Kondo, Ryo Nakagawa, Sadahisa Ogasawara, Ryosuke Muroyama, Shingo Nakamoto, Tatsuo Kanda, Hitoshi Maruyama, Jun Kato, Shoji Matsumoto, Takayoshi Arai, Shinichiro Motohashi, Naoya Kato

    Anticancer research   43 ( 3 )   1043 - 1052   2023.3

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    BACKGROUND/AIM: MHC-class I-related chain A (MICA) functions as a ligand for natural killer group D, an activating receptor on natural killer (NK) cells, and its expression correlates with the carcinogenesis and progression of hepatocellular carcinoma (HCC). Although membranous MICA (mMICA) activates NK cells, soluble forms of MICA (sMICA), shed by cleaving enzymes, such as A disintegrin and metalloprotease (ADAM) 9, suppress NK cells. Therefore, the prevention of MICA shedding through the inhibition of ADAM9 has the potential to activate cancer immunity. Although we have discovered several ADAM inhibitors, many did not sufficiently activate NK cells without being cytotoxic, and, thus, new ADAM9 inhibitor candidates are needed. MATERIALS AND METHODS: To identify possible compounds for drug development, chemical library screening (a total of 741 compounds) was conducted using a fluorescence assay. Compounds with reduced fluorescence intensity were used as hit compounds in a subsequent analysis. Their impact on sMICA and mMICA in HCC cell lines was assessed using ELISA and flow cytometry, respectively. The cytotoxicity of NK cells was also evaluated by co-culturing NK cells with HCC cells. RESULTS: CCL347, a symmetrical compound with five benzene rings, was identified as a hit compound. CCL347 significantly reduced sMICA levels in the culture medium supernatant with negligible cytotoxicity. Although mMICA was also reduced, CCL347 successfully enhanced NK cell cytotoxicity in co-cultures of NK cells and HCC cells. CONCLUSION: CCL347 has potential as a novel therapeutic drug for HCC.

    DOI: 10.21873/anticanres.16249

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  • Activated CTLA-4-independent immunosuppression of Treg cells disturbs CTLA-4 blockade-mediated antitumor immunity. Reviewed International journal

    Tomofumi Watanabe, Takamasa Ishino, Youki Ueda, Joji Nagasaki, Takuya Sadahira, Hiromichi Dansako, Motoo Araki, Yosuke Togashi

    Cancer science   114 ( 5 )   1859 - 1870   2023.2

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    Combination therapy with anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) monoclonal antibodies (mAbs) has dramatically improved the prognosis of patients with multiple types of cancer, including renal cell carcinoma (RCC). However, more than half of RCC patients fail to respond to this therapy. Regulatory T cells (Treg cells) are a subset of highly immunosuppressive CD4+ T cells that promote the immune escape of tumors by suppressing effector T cells in the tumor microenvironment (TME) through various mechanisms. CTLA-4 is constitutively expressed in Treg cells and is regarded as a key molecule for Treg cell-mediated immunosuppressive functions, suppressing antigen-presenting cells by binding to CD80/CD86. Reducing Treg cells in the TME with an anti-CTLA-4 mAb with antibody-dependent cellular cytotoxicity (ADCC) activity is considered an essential mechanism to achieve tumor regression. In contrast, we demonstrated that only CTLA-4 blockade without ADCC activity enhanced CD28 costimulatory signaling pathways in Treg cells and promoted Treg-cell proliferation in mouse models. CTLA-4 blockade also augmented CTLA-4-independent immunosuppressive functions, including cytokine production, leading to insufficient antitumor effects. Similar results were also observed in human peripheral blood lymphocytes and tumor-infiltrating lymphocytes from patients with RCC. Our findings highlight the importance of Treg-cell depletion to achieve tumor regression in response to CTLA-4 blockade therapies.

    DOI: 10.1111/cas.15756

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  • Somatic mutations can induce a noninflamed tumour microenvironment via their original gene functions, despite deriving neoantigens. Reviewed International journal

    Takamasa Ishino, Shusuke Kawashima, Etsuko Tanji, Toshihide Ueno, Youki Ueda, Sadahisa Ogasawara, Kazuhito Sato, Hiroyuki Mano, Soichiro Ishihara, Naoya Kato, Masahito Kawazu, Yosuke Togashi

    British journal of cancer   2023.2

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    BACKGROUND: Identifying biomarkers to predict immune checkpoint inhibitor (ICI) efficacy is warranted. Considering that somatic mutation-derived neoantigens induce strong immune responses, patients with a high tumour mutational burden reportedly tend to respond to ICIs. However, there are several conflicting data. Therefore, we focused on the original function of neoantigenic mutations and their impact on the tumour microenvironment (TME). METHODS: We evaluated 88 high-frequency microsatellite instability (MSI-H) colorectal cancers and analysed the function of the identified neoantigenic mutations and their influence on programmed cell death 1 (PD-1) blockade efficacy. The results were validated using The Cancer Genome Atlas (TCGA) datasets. RESULTS: We identified frameshift mutations in RNF43 as a common neoantigenic gene mutation in MSI-H tumours. However, loss-of-function RNF43 mutations induced noninflamed TME by activating the WNT/β-catenin signalling pathway. In addition, loss of RNF43 function induced resistance to PD-1 blockade even in neoantigen-rich tumours. TCGA dataset analyses demonstrated that passenger rather than driver gene mutations were related to the inflamed TME in diverse cancer types. CONCLUSIONS: We propose a novel concept of "paradoxical neoantigenic mutations" that can induce noninflamed TME through their original gene functions, despite deriving neoantigens, suggesting the significance of qualities as well as quantities in neoantigenic mutations.

    DOI: 10.1038/s41416-023-02165-6

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  • Miglustat, a glucosylceramide synthase inhibitor, mitigates liver fibrosis through TGF-β/Smad pathway suppression in hepatic stellate cells. Reviewed International journal

    Terunao Iwanaga, Tetsuhiro Chiba, Masato Nakamura, Tatsuya Kaneko, Junjie Ao, Na Qiang, Yaojia Ma, Jiaqi Zhang, Tadayoshi Kogure, Sae Yumita, Takamasa Ishino, Keita Ogawa, Motoyasu Kan, Miyuki Nakagawa, Kisako Fujiwara, Naoto Fujita, Takafumi Sakuma, Hiroaki Kanzaki, Keisuke Koroki, Yuko Kusakabe, Masanori Inoue, Kazufumi Kobayashi, Naoya Kanogawa, Soichiro Kiyono, Takayuki Kondo, Ryo Nakagawa, Sadahisa Ogasawara, Shingo Nakamoto, Ryosuke Muroyama, Jun Kato, Tatsuo Kanda, Hitoshi Maruyama, Naoya Mimura, Takuya Honda, Toshihiko Murayama, Hiroyuki Nakamura, Naoya Kato

    Biochemical and biophysical research communications   642   192 - 200   2023.1

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    Transforming growth factor (TGF)-β/Smad pathway is implicated in the pathogenesis of liver fibrosis, a condition characterized by excessive deposition of extracellular matrix (ECM) proteins such as collagen in response to chronic inflammation. It has been reported that ceramide regulates collagen production through TGF-β/Smad pathway activation. In this study, we examined whether miglustat, an inhibitor of glucosylceramide synthase, can suppress liver fibrosis by reducing TGF-β/Smad pathway activity. Human hepatic stellate cells (HHSteCs) were cultured with TGF-β and multiple miglustat concentrations to examine dose-dependent effects on the expression levels of ECM-related genes and Smad proteins. To evaluate the efficacy of miglustat for fibrosis mitigation, C57BL/6 mice were treated with carbon tetrachloride (CCl4) for 4 weeks to induce liver fibrosis, followed by combined CCl4 plus miglustat for a further 2 weeks. To examine if miglustat can also prevent fibrosis, mice were treated with CCl4 for 2 weeks, followed by CCl4 plus miglustat for 2 weeks. Miglustat dose-dependently downregulated expression of α-smooth muscle actin and ECM components in TGF-β-treated HHSteCs. Both phosphorylation and nuclear translocation of Smad2 and Smad3 were also suppressed by miglustat treatment. Sirius-Red staining and hydroxyproline assays of model mouse liver samples revealed that miglustat reduced fibrosis, an effect accompanied by decreased expression of ECM. Our findings suggest that miglustat can both prevent and reverse liver fibrosis by inhibiting TGF-β/Smad pathway.

    DOI: 10.1016/j.bbrc.2022.12.025

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  • Clinical effects and emerging issues of atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma from Japanese real‐world practice Reviewed International journal

    Miyuki Nakagawa, Masanori Inoue, Sadahisa Ogasawara, Susumu Maruta, Tomomi Okubo, Norio Itokawa, Yotaro Iino, Masamichi Obu, Yuki Haga, Atsuyoshi Seki, Yasuharu Kikuchi, Tadayoshi Kogure, Sae Yumita, Takamasa Ishino, Keita Ogawa, Kisako Fujiwara, Terunao Iwanaga, Naoto Fujita, Takafumi Sakuma, Ryuta Kojima, Hiroaki Kanzaki, Keisuke Koroki, Takashi Taida, Kazufumi Kobayashi, Soichiro Kiyono, Masato Nakamura, Naoya Kanogawa, Takayuki Kondo, Ryo Nakagawa, Shingo Nakamoto, Ryosuke Muroyama, Tetsuhiro Chiba, Ei Itobayashi, Masanori Atsukawa, Yoshihiro Koma, Ryosaku Azemoto, Kenji Ito, Hideaki Mizumoto, Masami Shinozaki, Jun Kato, Naoya Kato

    Cancer   129 ( 4 )   590 - 599   2022.11

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    BACKGROUND: Although the efficacy of atezolizumab has been demonstrated in randomized controlled trials, its long-term efficacy and association with adverse events in real-world practice are unknown. This study was designed to shed light on these issues. METHODS: In this multicenter retrospective study, data were collected from patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab in seven institutions in Japan. The authors focused on the efficacy and adverse events related to vascular endothelial growth factor (VEGF) inhibition. RESULTS: A total of 123 patients were enrolled in this study. The median progression-free survival (PFS) for the first-line treatment group was 8.0 months (95% confidence interval [CI], 6.1-9.9), whereas the median PFS for the second- or later-line treatment group was 4.1 months (95% CI, 2.6-5.7), which was significantly worse than that of the first-line treatment group (p = .005). Twenty-seven patients had interrupted bevacizumab treatment. Proteinuria accounted for the largest proportion of bevacizumab treatment interruptions. The cumulative incidence rate of bevacizumab interruption due to anti-VEGF-related adverse events was significantly higher in patients with hypertension and/or diabetes mellitus than in those without (p = .026). The landmark analysis showed that patients experienced bevacizumab interruption by 24 weeks from treatment initiation had poorer PFS than those who did not (p = .013). CONCLUSIONS: The PFS of atezolizumab plus bevacizumab as first-line treatment mostly replicates that of a global phase 3 trial. Interrupted bevacizumab treatment was more common in patients with hypertension and/or diabetes mellitus, which may be associated with worsening long-term PFS. PLAIN LANGUAGE SUMMARY: Atezolizumab plus bevacizumab has been the standard front line systemic therapy for advanced hepatocellular carcinoma. With the growing incidence of fatty liver due to metabolic syndrome as a background liver disease for hepatocellular carcinoma, the rate of comorbid hypertension and diabetes mellitus has been increasing accordingly. The present study demonstrated the cumulative incidence rate of bevacizumab interruption due to anti-VEGF-related adverse events was significantly higher in patients with hypertension and/or diabetes mellitus. The landmark analysis clarified that interruption of bevacizumab might be a risk of impaired efficacy of atezolizumab plus bevacizumab over the long term in patients with advanced hepatocellular carcinoma.

    DOI: 10.1002/cncr.34559

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    Other Link: https://onlinelibrary.wiley.com/doi/full-xml/10.1002/cncr.34559

  • 【免疫チェックポイント阻害薬の"耐性"に挑む がん免疫サイクルから見出す戦略】免疫チェックポイント阻害薬治療によるクローン進化

    石野 貴雅, 冨樫 庸介

    実験医学   40 ( 16 )   2587 - 2592   2022.10

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    がん細胞は免疫から逃避して自身に有利な腫瘍微小環境を構築する「がん免疫編集」により生存し増殖している。免疫チェックポイント阻害薬は抗腫瘍応答を担う細胞傷害性T細胞を活性化させることでがん細胞を排除して効果を発揮するが、がん細胞もさらに抗腫瘍免疫応答から逃れるために不均一な腫瘍微小環境下で自身に有利なクローンを選択することで進化を重ねている。免疫系もまた不均一な集団だが、免疫チェックポイント阻害薬を使用した際にがん細胞を直接攻撃する細胞傷害性T細胞クローンが拡大することが奏効において重要である。がんと免疫系のクロストークのなかで双方でどのようなクローンが選択され、進化しているかを理解することは、免疫チェックポイント阻害薬の奏効や耐性のメカニズムを解明するうえでも重要であると考えている。(著者抄録)

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  • Mechanisms of resistance to immune checkpoint inhibitors. Reviewed International journal

    Joji Nagasaki, Takamasa Ishino, Yosuke Togashi

    Cancer science   113 ( 10 )   3303 - 3312   2022.10

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    Immune checkpoint inhibitors (ICIs) are effective for various types of cancer, and their application has led to paradigm shifts in cancer treatment. While many patients can obtain clinical benefits from ICI treatment, a large number of patients are primarily resistant to such treatment or acquire resistance after an initial response. Thus, elucidating the resistance mechanisms is warranted to improve the clinical outcomes of ICI treatment. ICIs exert their antitumor effects by activating T cells in the tumor microenvironment. There are various resistance mechanisms, such as insufficient antigen recognition by T cells, impaired T-cell migration and/or infiltration, and reduced T-cell cytotoxicity, most of which are related to the T-cell activation process. Thus, we classify them into three main mechanisms: resistance mechanisms related to antigen recognition, T-cell migration and/or infiltration, and effector functions of T cells. In this review, we summarize these mechanisms of resistance to ICIs related to the T-cell activation process and progress in the development of novel therapies that can overcome resistance.

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  • 脈管侵襲を伴う進行肝細胞癌における薬物療法と適切な治療効果判定の検討

    井上 将法, 小笠原 定久, 石野 貴雅, 小川 慶太, 岩永 光巨, 宇野澤 秀美, 弓田 冴, 中川 美由貴, 藤原 希彩子, 神崎 洋彰, 興梠 慧輔, 小林 和史, 中村 昌人, 清野 宗一郎, 叶川 直哉, 近藤 孝行, 中川 良, 中本 晋吾, 室山 良介, 千葉 哲博, 加藤 順, 加藤 直也

    肝臓   63 ( Suppl.3 )   A780 - A780   2022.10

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  • その機能がnon-inflamedな腫瘍微小環境を誘導し得る逆説的なネオ抗原の存在(Paradoxical neoantigens; neontigens can paradoxically induce a non-inflamed tumor microenvironment via gene functions.)

    石野 貴雅, 上野 敏秀, 上田 優輝, 間野 博行, 石原 聡一郎, 加藤 直也, 河津 正人, 冨樫 庸介

    日本癌学会総会記事   81回   E - 2052   2022.9

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  • その機能がnon-inflamedな腫瘍微小環境を誘導し得る逆説的なネオ抗原の存在(Paradoxical neoantigens; neoantigens can paradoxically induce a non-inflamed tumor microenvironment via gene functions.)

    石野 貴雅, 上野 敏秀, 上田 優輝, 間野 博行, 石原 聡一郎, 加藤 直也, 河津 正人, 冨樫 庸介

    日本癌学会総会記事   81回   P - 2171   2022.9

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  • Liver biopsy technique in the era of genomic cancer therapies: a single-center retrospective analysis. Reviewed

    Yusuke Ozeki, Naoya Kanogawa, Sadahisa Ogasawara, Keita Ogawa, Takamasa Ishino, Miyuki Nakagawa, Kisako Fujiwara, Hidemi Unozawa, Terunao Iwanaga, Takafumi Sakuma, Naoto Fujita, Ryuta Kojima, Hiroaki Kanzaki, Keisuke Koroki, Kazufumi Kobayashi, Masato Nakamura, Soichiro Kiyono, Takayuki Kondo, Tomoko Saito, Ryo Nakagawa, Eiichiro Suzuki, Yoshihiko Ooka, Shingo Nakamoto, Ryosuke Muroyama, Akinobu Tawada, Tetsuhiro Chiba, Makoto Arai, Jun Kato, Jun-Ichiro Ikeda, Yuichi Takiguchi, Naoya Kato

    International journal of clinical oncology   27 ( 9 )   1459 - 1466   2022.9

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    BACKGROUND: With the evolution of personalized medicine in the field of oncology, which includes optimal treatment selection using next-generation sequencing-based companion diagnostic systems and tumor-agnostic treatments according to common biomarkers, a liver tumor biopsy technique that can obtain a sufficient specimen volume must be established. The current study aimed to evaluate the safety and availability of a liver tumor biopsy technique with multiple puncture sites made using a coaxial introducer needle and embolization with gelatin sponge particles. METHODS: Patients with primary or metastatic liver cancer who underwent liver tumor biopsies with puncture tract embolization using gelatin sponge (Spongel®) from October 2019 to September 2020 were included in the study. The complication and diagnostic rates were evaluated, and whether the specimen volume was sufficient for Foundation® CDx was investigated. RESULTS: In total, 96 patients were enrolled in this analysis. The median total number of puncture times per patient was 3 (range 1-8). The pathological diagnostic rate was 79.2%. Using the FoundationOne® CDx, specimens with a sufficient volume required for genomic medicine were collected in 84.9% of patients. The incidence rate of bleeding was 4.2% (n = 4), and only one patient presented with major bleeding requiring transfusion. CONCLUSIONS: Liver biopsy with puncture tract embolization using a gelatin sponge may be safe and effective for collecting specimens with a volume sufficient for modern cancer treatments.

    DOI: 10.1007/s10147-022-02195-9

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  • Durvalumab with or without tremelimumab combined with particle therapy for advanced hepatocellular carcinoma with macrovascular invasion: protocol for the DEPARTURE phase Ib trial. Reviewed International journal

    Sadahisa Ogasawara, Keisuke Koroki, Hirokazu Makishima, Masaru Wakatsuki, Asahi Takahashi, Sae Yumita, Miyuki Nakagawa, Takamasa Ishino, Keita Ogawa, Kisako Fujiwara, Terunao Iwanaga, Takafumi Sakuma, Naoto Fujita, Ryuta Kojima, Hiroaki Kanzaki, Kazufumi Kobayashi, Soichiro Kiyono, Masato Nakamura, Naoya Kanogawa, Tomoko Saito, Takayuki Kondo, Ryo Nakagawa, Shingo Nakamoto, Ryosuke Muroyama, Tetsuhiro Chiba, Yoshihito Ozawa, Yohei Kawasaki, Tomoya Kurokawa, Hideki Hanaoka, Hiroshi Tsuji, Naoya Kato

    BMJ open   12 ( 4 )   e059779   2022.4

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    INTRODUCTION: Advanced hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) has the worst prognosis among all phenotypes. This trial aims to evaluate whether treatment with durvalumab, alone or in combination with tremelimumab, plus particle therapy is a safe and synergistically effective treatment in patients with advanced HCC and MVI. METHODS AND ANALYSIS: This phase Ib, multicentre (two sites in Japan), open-label, single-arm, investigator-initiated clinical trial will assess durvalumab monotherapy in combination with particle therapy (cohort A) and that of durvalumab plus tremelimumab in combination with particle therapy (cohort B) for patients with advanced HCC with MVI. Cohort A will receive 1500 mg durvalumab every 4 weeks. Cohort B will receive 1500 mg durvalumab every 4 weeks in principle and 300 mg tremelimumab only on day 1 of the first cycle. Carbon-ion radiotherapy will be administered after day 8 of the first cycle. The primary endpoints are rates of any and severe adverse events, including dose-limiting toxicities (DLTs); secondary endpoints are overall survival, 6-month survival, objective response, 6-month progression-free survival and time to progression. Patients are initially enrolled into cohort A. If cohort A treatment is confirmed to be tolerated (ie, no DLT in three patients or one DLT in six patients), the trial proceeds to enrol more patients into cohort B. Similarly, if cohort B treatment is confirmed to be tolerated (ie, no DLT in three patients or one DLT in six patients), a total of 15 patients will be enrolled into cohort B. ETHICS AND DISSEMINATION: This study was approved by the ethics committees of the two participating institutions (Chiba University Hospital and National Institutes for Quantum (approval number: 2020040) and Radiological Science and Technology, QST Hospital (approval number: C20-001)). Participants will be required to provide written informed consent. Trial results will be reported in a peer-reviewed journal publication. TRIAL REGISTRATION NUMBER: jRCT2031210046.

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  • 高度の門脈圧亢進症を呈した門脈血栓症に対し経頸静脈的肝内門脈静脈短絡術(TIPS)が奏功した1例

    藤原 希彩子, 近藤 孝行, 弓田 冴, 小川 慶太, 石野 貴雅, 中川 美由貴, 宇野澤 秀美, 岩永 光巨, 藤田 尚人, 佐久間 崇文, 神崎 洋彰, 興梠 慧輔, 小林 和史, 中村 昌人, 清野 宗一郎, 叶川 直哉, 小笠原 定久, 中本 晋吾, 千葉 哲博, 加藤 順, 加藤 直也, 和田 武, 窪田 吉紘, 雑賀 厚至, 小泉 淳

    日本門脈圧亢進症学会雑誌   28 ( 1 )   77 - 82   2022.3

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    門脈血栓症は時として致死的な転機をたどる病態である。今回、高度の門脈圧亢進症を呈した亜急性門脈血栓症に対して経頸静脈的肝内門脈静脈短絡術(TIPS)が著効した1例を経験したので報告する。症例は56歳男性。腹痛を契機に近医を受診し、門脈本幹から肝内門脈右枝、上腸間膜静脈に至る広範囲の血栓を認め、当院紹介となった。前医で出血性十二指腸潰瘍の治療歴があったため、AT III製剤単独の投与を開始したが治療効果なく、胸腹水の増悪を認めた。そのため、経頸静脈的に肝内門脈から上腸間膜静脈にアプローチし血栓回収・ウロキナーゼ持続門注を開始した。門注後も血栓は溶解されず、下腸間膜静脈から右肝静脈へTIPSステントを留置した。その後、血流の求肝性変化、胸腹水の消失と低アルブミン血症の改善を認め、独歩での退院となった。血栓溶解療法に反応せず著明な門脈圧亢進症を呈している門脈血栓の症例においては、TIPSは治療選択肢に考慮するべきである。(著者抄録)

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  • Evolution of Survival Impact of Molecular Target Agents in Patients with Advanced Hepatocellular Carcinoma. Reviewed International journal

    Kazufumi Kobayashi, Sadahisa Ogasawara, Aya Takahashi, Yuya Seko, Hidemi Unozawa, Rui Sato, Shunji Watanabe, Michihisa Moriguchi, Naoki Morimoto, Satoshi Tsuchiya, Kenji Iwai, Masanori Inoue, Keita Ogawa, Takamasa Ishino, Terunao Iwanaga, Takafumi Sakuma, Naoto Fujita, Hiroaki Kanzaki, Keisuke Koroki, Masato Nakamura, Naoya Kanogawa, Soichiro Kiyono, Takayuki Kondo, Tomoko Saito, Ryo Nakagawa, Eiichiro Suzuki, Yoshihiko Ooka, Shingo Nakamoto, Akinobu Tawada, Tetsuhiro Chiba, Makoto Arai, Tatsuo Kanda, Hitoshi Maruyama, Kengo Nagashima, Jun Kato, Norio Isoda, Takeshi Aramaki, Yoshito Itoh, Naoya Kato

    Liver cancer   11 ( 1 )   48 - 60   2022.1

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    BACKGROUND AND AIMS: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is expected to improve as multiple molecular target agents (MTAs) are now available. However, the impact of the availability of sequential MTAs has not been fully verified yet. APPROACH AND RESULTS: We retrospectively collected the data on the whole clinical course of 877 patients who received any MTAs as first-line systemic therapy for advanced HCC between June 2009 and March 2019. The study population was divided into 3 groups according to the date of first-line MTA administration (period 1: 2009-2012, n = 267; period 2: 2013-2016, n = 352; period 3: 2017-2019, n = 258). Then, we compared the number of MTAs used, overall survival (OS), and MTA treatment duration among the 3 groups. Analysis was also performed separately for advanced-stage and nonadvanced-stage HCC. The proportion of patients who received multiple MTAs was remarkably increased over time (1.1%, 10.2%, and 42.6% in periods 1, 2, and 3, respectively, p < 0.001). The median OS times were prolonged to 10.4, 11.3, and 15.2 months in periods 1, 2, and 3, respectively (p = 0.016). Similarly, the MTA treatment durations were extended (2.7, 3.2, and 6.6 months in periods 1, 2, and 3, respectively; p < 0.001). We confirmed that the correlation between OS and MTA treatment duration was strengthened (period 1: 0.395, period 2: 0.505, and period 3: 0.667). All these trends were pronounced in the patients with advanced-stage HCC but limited in the patients with nonadvanced-stage HCC. CONCLUSIONS: The availability of multiple MTAs had steadily improved the prognosis of patients with advanced HCC patients, particularly advanced-stage HCC patients.

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  • Effect of Atezolizumab plus Bevacizumab in Patients with Hepatocellular Carcinoma Harboring CTNNB1 Mutation in Early Clinical Experience. Reviewed International journal

    Keita Ogawa, Hiroaki Kanzaki, Tetsuhiro Chiba, Junjie Ao, Na Qiang, Yaojia Ma, Jiaqi Zhang, Sae Yumita, Takamasa Ishino, Hidemi Unozawa, Motoyasu Kan, Terunao Iwanaga, Miyuki Nakagawa, Kisako Fujiwara, Naoto Fujita, Takafumi Sakuma, Keisuke Koroki, Yuko Kusakabe, Kazufumi Kobayashi, Naoya Kanogawa, Soichiro Kiyono, Masato Nakamura, Takayuki Kondo, Tomoko Saito, Ryo Nakagawa, Sadahisa Ogasawara, Eiichiro Suzuki, Shingo Nakamoto, Ryosuke Muroyama, Tatsuo Kanda, Hitoshi Maruyama, Naoya Mimura, Jun Kato, Shinichiro Motohashi, Naoya Kato

    Journal of Cancer   13 ( 8 )   2656 - 2661   2022

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    Atezolizumab plus bevacizumab (ATZ/BV) treatment is a combined immunotherapy consisting of immune checkpoint inhibitor (ICI) and anti-vascular endothelial growth factor monoclonal antibody, which has brought a major paradigm shift in the treatment of unresectable hepatocellular carcinoma (HCC). Gain-of-function mutation of CTNNB1 contributes to resistance of ICI monotherapy through the framework of non-T-cell-inflamed tumor microenvironment. However, whether CTNNB1 mutation renders resistance to ATZ/BV similar to ICI monotherapy remains to be elucidated. In this study, a liquid biopsy sample in plasma of 33 patients with HCC treated with ATZ/BV was subjected to droplet digital PCR for detecting hotspot mutations at the exon 3 of CTNNB1 locus. A total of eight patients (24.2%) exhibited at least one CTNNB1 mutation. The objective response rate (ORR) in patients with wild-type (WT) and mutant (MT) CTNNB1 was 8.0% and 12.5%, respectively, and the disease control rate (DCR) was 68.0% and 87.5%, respectively. No significant difference in both ORR and DCR has been observed between the two groups. The median progression-free survival in patients with WT and MT CTNNB1 was 6.6 and 7.6 months, respectively (not statistically significant). Similarly, no significant difference in overall survival has been observed between patients with WT and MT CTNNB1 (13.6 vs. 12.3 months). In conclusion, the treatment effect of ATZ/BV in patients with HCC with MT CTNNB1 was comparable to those patients with WT CTNNB1. These results implicate that BV added to ATZ might improve immunosuppressive tumor microenvironment caused by CTNNB1 mutation.

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  • 進行肝細胞癌の薬物治療における抗腫瘍効果判定の際の脈管浸潤の位置づけ 現状と今後の課題

    小林 和史, 小笠原 定久, 石野 貴雅, 小川 慶太, 岩永 光巨, 宇野澤 秀美, 中川 美由貴, 藤原 希彩子, 佐久間 崇文, 藤田 尚人, 神崎 洋彰, 興梠 慧輔, 中村 昌人, 清野 宗一郎, 叶川 直哉, 近藤 孝行, 齊藤 朋子, 中川 良, 鈴木 英一郎, 大岡 美彦, 中本 晋吾, 千葉 哲博, 加藤 順, 加藤 直也

    肝臓   62 ( Suppl.3 )   A754 - A754   2021.11

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  • 進行肝細胞癌に対するAtezolizumab/Bevacizumab併用療法の実臨床での使用経験

    中川 美由貴, 小笠原 定久, 大部 誠道, 大久保 智美, 芳賀 祐規, 畦元 亮作, 厚川 正則, 伊藤 健治, 石野 貴雅, 小川 慶太, 藤原 希彩子, 宇野澤 秀美, 岩永 光巨, 佐久間 崇文, 藤田 尚人, 興梠 慧輔, 神崎 洋彰, 小林 和史, 清野 宗一郎, 中村 昌人, 叶川 直哉, 齊藤 朋子, 近藤 孝行, 中本 晋吾, 千葉 哲博, 加藤 順, 加藤 直也

    肝臓   62 ( Suppl.3 )   A757 - A757   2021.11

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  • Exploring microsatellite instability in patients with advanced hepatocellular carcinoma and its tumor microenvironment. Reviewed International journal

    Shohei Mukai, Hiroaki Kanzaki, Sadahisa Ogasawara, Takamasa Ishino, Keita Ogawa, Miyuki Nakagawa, Kisako Fujiwara, Hidemi Unozawa, Terunao Iwanaga, Takafumi Sakuma, Naoto Fujita, Keisuke Koroki, Kazufumi Kobayashi, Naoya Kanogawa, Soichiro Kiyono, Masato Nakamura, Takayuki Kondo, Tomoko Saito, Ryo Nakagawa, Eiichiro Suzuki, Yoshihiko Ooka, Ryosuke Muroyama, Shingo Nakamoto, Akinobu Tawada, Tetsuhiro Chiba, Makoto Arai, Jun Kato, Manayu Shiina, Masayuki Ota, Jun-Ichiro Ikeda, Yuichi Takiguchi, Masayuki Ohtsuka, Naoya Kato

    JGH open : an open access journal of gastroenterology and hepatology   5 ( 11 )   1266 - 1274   2021.11

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    BACKGROUND AND AIM: Immune checkpoint inhibitors and their combination with other agents have recently been available in advanced hepatocellular carcinoma (HCC). Hence, a thorough understanding of the tumor microenvironment based on tumor samples is yet to be achieved. This study aimed to explore the tumor microenvironment in advanced HCC in terms of microsatellite instability-high (MSI-H) by using tumor samples from advanced HCC patients eligible for systemic therapy. METHODS: MSI-H was assessed by polymerase chain reaction, and the expression of mismatch repair proteins, PD-L1, CD8, VEGF, and HLA-class1 was evaluated by immunohistochemistry. Whole-exome sequencing was performed for MSI-H tumor samples. RESULTS: Of 50 patients, one (2.0%) was confirmed with MSI-H. In the MSI-H advanced HCC tumor, a high tumor mutation burden, infiltration of CD8+ lymphocytes, and low expression of VEGF were identified. Although PD-L1 expression was negative, there was shrinkage of tumor following pembrolizumab. However, another tumor nonresponsive to pembrolizumab was present simultaneously. Checking the Cancer Genome Atlas (TCGA) database, we found a similar case to this patient. The TCGA case had unique gene features of miR-21 and miR-155 overexpression and hypermethylation of the MSH2 gene. CONCLUSION: We identified a very small number of MSI-H cases in HCC using one tumor biopsy sample for each patient with advanced HCC. In addition, epigenetic aberrations possibly lead to MSI-H in HCC patients. Since different HCC clones might coexist in the liver, sampling from multiple tumors should be considered to clarify the true proportion of MSI-H in HCC and to analyze tumor microenvironments.

    DOI: 10.1002/jgh3.12660

    PubMed

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Books

  • 免疫チェックポイント阻害薬治療によるクローン進化

    石野貴雅, 冨樫庸介

    実験医学 40 (16): 2587-92  2022.10 

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  • がん免疫併用療法のあり方-がんの免疫チェックポイント阻害薬への抵抗性獲得のメカニズムと,その克服の手段としての併用療法の現状-

    石野貴雅, 冨樫庸介

    腫瘍内科 30(1): 59-66  2022.7 

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  • Treg細胞の活性化CTLA-4非依存性免疫抑制によるCTLA-4遮断の不安定な抗腫瘍効果(Disturbed anti-tumor effect of CTLA-4 blockade by activated CTLA-4-independent immunosuppression of Treg cells)

    渡部 智文, 石野 貴雅, 上田 優輝, 長崎 譲慈, 河田 達志, 定平 卓也, 岩田 健宏, 片山 聡, 枝村 康平, 小林 泰之, 團迫 浩方, 荒木 元朗, 冨樫 庸介

    西日本泌尿器科学会総会抄録集   75回   185 - 185   2023.11

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  • ナルメフェン投与の単一内科での投与成績と今後の課題

    清野宗一郎, 小暮禎祥, 藤本健太郎, 弓田冴, 石野貴雅, 小川慶太, 藤原希彩子, 中川美由貴, 岩永光巨, 興梠慧輔, 神崎洋彰, 小林和史, 井上将法, 中村昌人, 叶川直哉, 近藤孝行, 小笠原定久, 中本晋吾, 千葉哲博, 加藤直也

    日本消化器病学会雑誌(Web)   120   2023

  • 【免疫チェックポイント阻害薬の"耐性"に挑む がん免疫サイクルから見出す戦略】免疫チェックポイント阻害薬治療によるクローン進化

    石野 貴雅, 冨樫 庸介

    実験医学   40 ( 16 )   2587 - 2592   2022.10

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    がん細胞は免疫から逃避して自身に有利な腫瘍微小環境を構築する「がん免疫編集」により生存し増殖している。免疫チェックポイント阻害薬は抗腫瘍応答を担う細胞傷害性T細胞を活性化させることでがん細胞を排除して効果を発揮するが、がん細胞もさらに抗腫瘍免疫応答から逃れるために不均一な腫瘍微小環境下で自身に有利なクローンを選択することで進化を重ねている。免疫系もまた不均一な集団だが、免疫チェックポイント阻害薬を使用した際にがん細胞を直接攻撃する細胞傷害性T細胞クローンが拡大することが奏効において重要である。がんと免疫系のクロストークのなかで双方でどのようなクローンが選択され、進化しているかを理解することは、免疫チェックポイント阻害薬の奏効や耐性のメカニズムを解明するうえでも重要であると考えている。(著者抄録)

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  • その機能がnon-inflamedな腫瘍微小環境を誘導し得る逆説的なネオ抗原の存在(Paradoxical neoantigens; neoantigens can paradoxically induce a non-inflamed tumor microenvironment via gene functions.)

    石野 貴雅, 上野 敏秀, 上田 優輝, 間野 博行, 石原 聡一郎, 加藤 直也, 河津 正人, 冨樫 庸介

    日本癌学会総会記事   81回   P - 2171   2022.9

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  • その機能がnon-inflamedな腫瘍微小環境を誘導し得る逆説的なネオ抗原の存在(Paradoxical neoantigens; neontigens can paradoxically induce a non-inflamed tumor microenvironment via gene functions.)

    石野 貴雅, 上野 敏秀, 上田 優輝, 間野 博行, 石原 聡一郎, 加藤 直也, 河津 正人, 冨樫 庸介

    日本癌学会総会記事   81回   E - 2052   2022.9

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  • レンバチニブの長期継続を目指した肝細胞癌治療のマネジメント

    渡部 太郎, 興梠 慧輔, 小笠原 定久, 小暮 禎祥, 弓田 冴, 小川 慶太, 石野 貴雅, 中川 美由貴, 藤原 希彩子, 宇野澤 秀美, 岩永 光巨, 藤田 尚人, 佐久間 崇文, 神崎 洋彰, 井上 将法, 小林 和史, 清野 宗一郎, 叶川 直哉, 中村 昌人, 齊藤 朋子, 近藤 孝行, 中本 晋吾, 千葉 哲博, 加藤 直也

    肝胆膵   85 ( 2 )   262 - 263   2022.8

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  • 【がん免疫療法の展望:免疫チェックポイント阻害薬の併用療法に中心に】がん免疫併用療法のあり方 がんの免疫チェックポイント阻害薬への抵抗性獲得のメカニズムと、その克服の手段としての併用療法の現状

    石野 貴雅, 冨樫 庸介

    腫瘍内科   30 ( 1 )   59 - 66   2022.7

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  • 進行肝細胞癌に対するシーケンシャル療法におけるカボザンチニブ治療の実際

    神崎 洋彰, 小笠原 定久, 吉田 亮伊, 吉埜 稜平, 弓田 冴, 石野 貴雅, 小川 慶太, 中川 美由貴, 藤原 希彩子, 宇野澤 秀美, 岩永 光巨, 佐久間 崇文, 藤田 尚人, 興梠 慧輔, 小林 和史, 清野 宗一郎, 叶川 直哉, 中村 昌人, 齊藤 朋子, 近藤 孝行, 中川 良, 中本 晋吾, 室山 良介, 千葉 哲博, 加藤 直也

    肝胆膵   85 ( 1 )   144 - 145   2022.7

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  • グルコシルセラミド合成酵素阻害薬の肝線維化予防および改善効果に関する検討

    岩永 光巨, 千葉 哲博, 敖 俊傑, 強 娜, 小川 慶太, 石野 貴雅, 菅 元泰, 佐久間 崇文, 神崎 洋彰, 興梠 慧輔, 小林 和史, 中村 昌人, 清野 宗一郎, 叶川 直哉, 近藤 孝行, 中川 良, 小笠原 定久, 室山 良介, 中本 晋吾, 加藤 直也

    肝臓   63 ( Suppl.1 )   A328 - A328   2022.4

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    J-GLOBAL

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  • 進行肝細胞癌の脈管浸潤進展における治療効果判定基準の改訂の必要性

    宇野澤 秀美, 小笠原 定久, 小林 和史, 石野 貴雅, 小川 慶太, 藤原 希彩子, 中川 美由貴, 岩永 光巨, 藤田 尚人, 佐久間 崇文, 神崎 洋彰, 興梠 慧輔, 中村 昌人, 清野 宗一郎, 叶川 直哉, 近藤 孝行, 中本 晋吾, 千葉 哲博, 加藤 順, 加藤 直也

    肝胆膵   84 ( 4 )   540 - 541   2022.4

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  • 肝細胞癌の患者におけるGas6とsAxlのバイオマーカーとしての意義の検討

    佐久間 崇文, 千葉 哲博, 神崎 洋彰, 小川 慶太, 石野 貴雅, 敖 俊杰, 強 娜, 馬 瑤佳, 張 家祺, 岩永 光巨, 菅 元泰, 中村 昌人, 中川 良, 加藤 順, 加藤 直也

    日本分子腫瘍マーカー研究会誌   37   8 - 9   2022

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  • 腹水注入針を介した電極針の誘導が有効であった尾状葉肝細胞癌に対するCTガイド下RFAの2例

    弓田 冴, 叶川 直哉, 石野 貴雅, 小川 慶太, 岩永 光臣, 宇野澤 秀美, 藤原 季彩子, 中川 美由貴, 佐久間 崇文, 藤田 尚人, 神崎 洋彰, 興梠 慧輔, 小林 和史, 中村 昌人, 清野 宗一郎, 近藤 孝行, 齋藤 朋子, 中川 良, 小笠原 定久, 中本 晋吾, 千葉 哲博, 加藤 直也

    肝臓   62 ( Suppl.3 )   A765 - A765   2021.11

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  • 【肝癌診療2021 アテゾリズマブ+ベバシズマブ登場後の展開】有害事象の実際(アテゾリズマブ・ベバシズマブ併用療法) 全国実臨床の副作用報告を踏まえて

    堀尾 亮輔, 小笠原 定久, 藤本 真徳, 小川 慶太, 石野 貴雅, 藤原 希彩子, 中川 美由貴, 宇野澤 秀美, 岩永 光巨, 藤田 尚人, 佐久間 崇文, 神崎 洋彰, 興梠 慧輔, 小林 和史, 清野 宗一郎, 中村 昌人, 叶川 直哉, 齊藤 朋子, 近藤 孝行, 中本 晋吾, 千葉 哲博, 加藤 順, 横手 幸太郎, 加藤 直也

    肝臓クリニカルアップデート   7 ( 1 )   19 - 24   2021.10

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    Language:Japanese   Publisher:医学図書出版(株)  

    2020年9月、本邦においてアテゾリズマブ・ベバシズマブ併用療法が切除不能な肝細胞癌の一次治療薬として保険承認され、実臨床で用いられるようになった。本邦の実臨床で認められた有害事象は、第III相試験(IMbrave150試験)と同様の傾向があったものの、IMbrave150試験では経験しなかった免疫関連有害事象(irAE)も散見されている。irAEは、これまでの分子標的治療薬では経験のない有害事象が少なくなく、多種多様な有害事象が報告されている。免疫療法が先行して開発された他癌腫での経験から学び、複数の診療科の専門医、看護師、薬剤師などといった多職種との連携を構築しながら診療にあたる必要があるだろう。(著者抄録)

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    Other Link: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J06599&link_issn=&doc_id=20211101360003&doc_link_id=%2Faa6kancd%2F2021%2F000701%2F004%2F0019b0024%26dl%3D3&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faa6kancd%2F2021%2F000701%2F004%2F0019b0024%26dl%3D3&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_4.gif

  • 肝細胞癌の患者におけるGas6とsAxlのバイオマーカーとしての意義の検討

    佐久間 崇文, 千葉 哲博, 神崎 洋彰, 小川 慶太, 石野 貴雅, 敖 俊杰, 強 娜, 馬 瑤佳, 張 家祺, 岩永 光巨, 菅 元泰, 中村 昌人, 中川 良, 加藤 順, 加藤 直也

    日本分子腫瘍マーカー研究会プログラム・講演抄録   41回   42 - 43   2021.9

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  • 直接穿刺によるフォーム硬化療法が奏功した結腸ストーマ静脈瘤の1例

    藤原 希彩子, 近藤 孝行, 宇野澤 秀美, 小川 慶太, 石野 貴雅, 中川 美由貴, 岩永 光巨, 藤田 尚人, 佐久間 崇文, 神崎 洋彰, 興梠 慧輔, 小林 和史, 中村 昌人, 清野 宗一郎, 叶川 直哉, 小笠原 定久, 中本 晋吾, 千葉 哲博, 加藤 順, 加藤 直也

    日本消化器病学会関東支部例会プログラム・抄録集   365回   33 - 33   2021.7

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  • 肝細胞癌診療におけるmodified ALBIの有用性の検討

    石野 貴雅, 井上 将法, 杉村 薫, 鈴木 宏將, 宮城島 大輔, 久保田 教生, 中川 彰彦, 菊池 保治, 篠崎 正美

    千葉医学雑誌   96 ( 6 )   139 - 139   2020.12

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  • 肝細胞癌診療におけるmodified ALBIの有用性の検討

    石野 貴雅, 井上 将法, 杉村 薫, 鈴木 宏將, 宮城島 大輔, 久保田 教生, 中川 彰彦, 菊池 保治, 篠崎 正美

    日本消化器病学会雑誌   117 ( 臨増大会 )   A715 - A715   2020.10

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  • 20年来の自己免疫性肝炎(AIH)経過中に出現した細胆管細胞癌からの考察

    石野 貴雅, 篠崎 正美, 鈴木 宏將, 井上 将法, 宮城島 大輔, 久保田 教生, 中川 彰彦, 菊池 保治

    日本消化器病学会関東支部例会プログラム・抄録集   358回   45 - 45   2020.2

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  • 消火器口腔内噴射による腐食性食道炎・胃炎後狭窄で栄養投与経路の確保に難渋した1例

    堀尾 亮輔, 橘川 嘉夫, 石野 貴雅, 小関 寛隆, 畠山 一樹, 宮本 禎浩, 三田 恭義, 有本 昇平, 山本 恭平

    日本内科学会関東地方会   648回   52 - 52   2019.2

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Presentations

  • その機能がnon-inflamedな腫瘍微小環境を誘導し得る逆説的なネオ抗原の存在

    石野貴雅, 上野敏秀, 上田優輝, 間野博行, 石原聡一郎, 加藤直也, 河津正人, 冨樫庸介

    第81回日本癌学会学術総会  2022.9 

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Awards

  • 令和5年度 岡山医学会賞(がん研究奨励賞(林原賞・山田賞))

    2024.3  

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  • JCA若手研究者ポスター賞

    2022.10   日本癌学会  

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  • 船越龍太賞

    2021  

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Research Projects

  • 新規モデル動物による異常ミトコンドリアspreadingの詳細解明

    Grant number:JPMJAX2321  2023.10 - 2026.03

    国立研究開発法人 科学技術振興機構  ACT-X 

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    Authorship:Principal investigator 

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  • Investigation of anti-tumor immune response through qualitative evaluation of neoantigens

    Grant number:21K20859  2021.08 - 2023.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Research Activity Start-up  Grant-in-Aid for Research Activity Start-up

    石野 貴雅

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    Grant amount:\3120000 ( Direct expense: \2400000 、 Indirect expense:\720000 )

    腫瘍は免疫系からの逃避機構として抑制性の免疫チェックポイント分子を利用しており、抗PD-1/PD-L1抗体といった免疫チェックポイント阻害剤はT細胞を活性化することで効果を発揮する。そのため抗腫瘍免疫においては腫瘍と直接対峙している腫瘍浸潤T細胞が重要である。T細胞の活性化には体細胞変異に由来するネオ抗原が重要であり、これまでに体細胞変異の量的な評価で免疫チェックポイント奏功を予測する試みがなされてきたが、それだけでは不十分であり、ネオ抗原の質的評価が腫瘍微小環境に与える影響を明らかにする必要がある。
    大腸癌88例のゲノム解析を行い、ネオ抗原を同定した。しかしながら、そのネオ抗原を有する大腸癌の免疫応答が低く、質的にT細胞活性を抑制していることが示唆された。実験的にもそのネオ抗原が逆説的にnon-inflamedな腫瘍微小環境をもたらすことを立証した。今後はTCGA等の公共データセットでも検証したうえで、従来とは異なる方法での質的な評価も加味したネオ抗原同定方法を目指し、ネオ抗原を質・量の両面から正確に評価し免疫チェックポイント阻害剤奏功に有用なバイオマーカーの構築を試みたいと考えている。

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