2018 Fiscal Year Annual Research Report
Boosting PD-1 blockade cancer immunotherapy by modulating T cell metabolism
| Project/Area Number |
17F17119
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| Research Institution | Kyoto University |
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Principal Investigator |
本庶 佑 京都大学, 高等研究院, 特別教授 (80090504)
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| Co-Investigator(Kenkyū-buntansha) |
CHOWDHURY PARTHA 京都大学, 高等研究院, 外国人特別研究員
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| Project Period (FY) |
2017-04-26 – 2019-03-31
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| Keywords | cancer immunotherapy |
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| 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.
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| Research Progress Status |
平成30年度が最終年度であるため、記入しない。
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| 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。
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Research Products
(3 results)
