キラーＴ細胞のエネルギー代謝機構の解析とＰＤ－１阻害がん免疫治療の効果予測

• 研究課題/領域番号: 18J15051
• 研究種目: 特別研究員奨励費
• 配分区分: 補助金
• 応募区分: 国内
• 研究分野: 免疫学
• 研究機関: 京都大学
• 研究代表者: Kumar Alok 京都大学, 医学研究科, 特別研究員(DC2)
• 研究期間 (年度): 2018-04-25 – 2020-03-31
• 研究課題ステータス: 完了 (2019年度)
• 配分額: 1,900千円 (直接経費: 1,900千円); 2019年度: 900千円 (直接経費: 900千円); 2018年度: 1,000千円 (直接経費: 1,000千円)
• キーワード: PD-1 / Immunosupression / PGC-1alpha / Biomarker / Mitochondrial activation / biomarker / cancer immunotherapy

研究実績の概要

We classified unresponsiveness reasons into i). unresponsvieness because of local reasons ii). unresponsiveness because of having systemic immunosuppressive property (SIP). In addition, we found immune response after PD-1 blockade is associated with mitochondrial activation. Based on this result, we concluded that mitochondrial activation could be biomarker to identify responder and nonresponders. Further, we found SIP-positive tumors release non-proteinaceous small molecule that inhibit mitochondrial activation and proliferation of T cells. Bezafibrate when used alongwith culture superntant cancels the suppressive effect of supernatnat. Bezafibrate treatment alongwith PD-1 blockade enhances the survival of host bearing SIP-positive tumor compared to PD-1 blockade alone.

現在までの達成度 (段落)

令和元年度が最終年度であるため、記入しない。

今後の研究の推進方策

令和元年度が最終年度であるため、記入しない。

研究成果

• [雑誌論文] Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy (2020)
  • 著者名/発表者名: Kumar A, Chamoto K, Chowdhury PS, Honjo T
  • 雑誌名: eLife 巻: 9 ページ: 1-21
  • DOI: 10.7554/elife.52330
  • NAID: 120006936324
  • 査読あり / オープンアクセス / 国際共著
• [雑誌論文] Synergistically Triggers Reactive Oxygen Species and DNA Damage and Inhibits Salmonella enterica subsp. Enterica Serovar Typhi and Vibrio fluvialis (2019)
  • 著者名/発表者名: Ghosh, T., Srivastava, S. K. Gaurav, A., Kumar, A., Kumar, P., Yadav, A. S., Pathania,, R., Navani, N. K.
  • 雑誌名: Applied and Environmental Microbiology 巻: 85 (4) 号: 4
  • DOI: 10.1128/aem.02487-18
• [雑誌論文] PPAR-Induced Fatty Acid Oxidation in T Cells Increases the Number of Tumor-Reactive CD8+ T Cells and Facilitates Anti–PD-1 Therapy (2018)
  • 著者名/発表者名: Chowdhury, P. S., Chamoto, K., Kumar. A., Honjo, T
  • 雑誌名: Cancer Immunology Research 巻: 6 ページ: 1375-1387
  • 査読あり
• [学会発表] Inhibition of mitochondria by tumor-derived small molecule leads to systemic unresponsiveness to PD-1 blockade therapy (2019)
  • 著者名/発表者名: Alok Kumar, Kenji Chamoto, Tasuku Honjo
  • 学会等名: 78th Annual Meeting of Japanese Cancer Association (JCA)
• [学会発表] Bezafibrate enhances PD-1 blockade efficacy by activating mitochondrial biogenesis and effector function of CTLs (2018)
  • 著者名/発表者名: Kumar, A.
  • 学会等名: The 77th Annual Meeting of Japanese Cancer Association
• [学会発表] Mechanistic analysis of unresponsiveness to the PD-1 blockade therapy (2018)
  • 著者名/発表者名: Kumar, A.
  • 学会等名: Immunocon 2018 (The 45th Annual conference of the Indian Immunology Society, New Delhi)
• [学会発表] Mechanistic analysis of unresponsiveness to the PD-1 blockade therapy (2018)
  • 著者名/発表者名: Kumar, A.
  • 学会等名: The 9th Annual ISAJ Symposium (by Indian Scientists Association in Japan)