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Boosting PD-1 blockade cancer immunotherapy by modulating T cell metabolism

Research Project

Project/Area Number 17F17119
Research Category

Grant-in-Aid for JSPS Fellows

Allocation TypeSingle-year Grants
Section外国
Research Field Immunology
Research InstitutionKyoto University

Principal Investigator

本庶 佑  京都大学, 高等研究院, 特別教授 (80090504)

Co-Investigator(Kenkyū-buntansha) CHOWDHURY PARTHA  京都大学, 高等研究院, 外国人特別研究員
Project Period (FY) 2017-04-26 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2018: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2017: ¥1,200,000 (Direct Cost: ¥1,200,000)
Keywordscancer immunotherapy / PD-1 blockade
Outline of Annual Research Achievements

Recently blockade of a key negative regulator (PD-1) of immune system using antibody has led to a paradigm shift in the field of cancer drug discovery, owing to its durable effect against a wide variety of cancers and is termed as PD-1 blockade cancer immunotherapy. However, a substantial number of patients do not respond to this therapy. Thus, combination therapy to improve PD-1 blockade efficacy must be developed. To overcome the low response rate of PD-1 blockade therapy, various combinations have been used. But, many clinical trial reports have not shown encouraging results. We recently demonstrated that activation of PGC-1α, a key regulator of mitochondrial biogenesis, /peroxisome proliferator-activated receptors (PPARs) by bezafibrate improves the efficacy of PD-1 blockade. However, the mechanism of anti-tumor immunity development by activation of the PPAR pathway remains unknown. In this study, we investigated the effect of bezafibrate on phenotype of effector T cells and its mitochondrial activities followed by investigation of the molecular mechanism of how bezafibrate modulates the differentiation of CTLs and enhances T cell-based anti-tumor immunity. We found that bezafibrate upregulates fatty acid oxidation and inhibits the apoptosis of effector T cells. This effect of bezafibrate on the effector phase resulted in an increased number of effector T cells and augmentation of tumoricidal effect by PD-1 blockade. Therefore, PPAR signal activation in T cells may be a promising strategy for PD-1 blockade combination therapy.

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (3 results)

All 2018

All Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (2 results)

  • [Journal Article] PPAR-induced fatty acid oxidation in T cells ameliorates the antitumor activity of PD-1 blockade by increasing the number of tumor-reactive CD8+ T cells2018

    • Author(s)
      Chowdhury, P. S., Chamoto, K., Kumar. A., Honjo, T
    • Journal Title

      Cancer Immunology Research

      Volume: 6 Pages: 1375-1387

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Boosting fatty acid oxidation by PPAR signal activation enhances CTL longevity and the efficacy of PD-1 blockade2018

    • Author(s)
      Chowdhury, P. S.
    • Organizer
      Annual Meeting of the Japanese Cancer Association
    • Related Report
      2018 Annual Research Report
  • [Presentation] Boosting fatty acid oxidation by PPAR signal activation with bezafibrate enhances killer T cells longevity and the efficacy of PD-1 blockade2018

    • Author(s)
      Chowdhury, P. S.
    • Organizer
      Immunocon 2018, Annual meeting of Indian Immunology Society
    • Related Report
      2018 Annual Research Report

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Published: 2017-05-25   Modified: 2024-03-26  

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