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

• Project/Area Number: 18J15051
• Research Category: Grant-in-Aid for JSPS Fellows
• Allocation Type: Single-year Grants
• Section: 国内
• Research Field: Immunology
• Research Institution: Kyoto University
• Principal Investigator: Kumar Alok 京都大学, 医学研究科, 特別研究員(DC2)
• Project Period (FY): 2018-04-25 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥1,900,000 (Direct Cost: ¥1,900,000); Fiscal Year 2019: ¥900,000 (Direct Cost: ¥900,000); Fiscal Year 2018: ¥1,000,000 (Direct Cost: ¥1,000,000)
• Keywords: PD-1 / Immunosupression / PGC-1alpha / Biomarker / Mitochondrial activation / biomarker / cancer immunotherapy

Outline of Annual Research Achievements

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.

Research Progress Status

令和元年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和元年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy (2020)
  • Author(s): Kumar A, Chamoto K, Chowdhury PS, Honjo T
  • Journal Title: eLife Volume: 9 Pages: 1-21
  • DOI: 10.7554/elife.52330
  • NAID: 120006936324
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Synergistically Triggers Reactive Oxygen Species and DNA Damage and Inhibits Salmonella enterica subsp. Enterica Serovar Typhi and Vibrio fluvialis (2019)
  • Author(s): Ghosh, T., Srivastava, S. K. Gaurav, A., Kumar, A., Kumar, P., Yadav, A. S., Pathania,, R., Navani, N. K.
  • Journal Title: Applied and Environmental Microbiology Volume: 85 (4) Issue: 4
  • DOI: 10.1128/aem.02487-18
• [Journal Article] PPAR-Induced Fatty Acid Oxidation in T Cells Increases the Number of Tumor-Reactive CD8+ T Cells and Facilitates Anti–PD-1 Therapy (2018)
  • Author(s): Chowdhury, P. S., Chamoto, K., Kumar. A., Honjo, T
  • Journal Title: Cancer Immunology Research Volume: 6 Pages: 1375-1387
  • Peer Reviewed
• [Presentation] Inhibition of mitochondria by tumor-derived small molecule leads to systemic unresponsiveness to PD-1 blockade therapy (2019)
  • Author(s): Alok Kumar, Kenji Chamoto, Tasuku Honjo
  • Organizer: 78th Annual Meeting of Japanese Cancer Association (JCA)
• [Presentation] Bezafibrate enhances PD-1 blockade efficacy by activating mitochondrial biogenesis and effector function of CTLs (2018)
  • Author(s): Kumar, A.
  • Organizer: The 77th Annual Meeting of Japanese Cancer Association
• [Presentation] Mechanistic analysis of unresponsiveness to the PD-1 blockade therapy (2018)
  • Author(s): Kumar, A.
  • Organizer: Immunocon 2018 (The 45th Annual conference of the Indian Immunology Society, New Delhi)
• [Presentation] Mechanistic analysis of unresponsiveness to the PD-1 blockade therapy (2018)
  • Author(s): Kumar, A.
  • Organizer: The 9th Annual ISAJ Symposium (by Indian Scientists Association in Japan)