期刊
CANCER IMMUNOLOGY RESEARCH
卷 6, 期 11, 页码 1375-1387出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-18-0095
关键词
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资金
- AMED [JP17cm0106302, JP17gm0710012, JP171k1403006]
- Tang Prize Foundation
- JSPS KAKENHI [JP16H06149, 17K19593, 17F17119]
- Cell Science Foundation
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [17K19593, 17F17119] Funding Source: KAKEN
Although PD-1 blockade cancer immunotherapy has shown potential for a wide range of patients with cancer, its efficacy is limited, in part, due to the loss of effector cytotoxic T lymphocytes (CTLs) via terminal differentiation-induced apoptosis. We previously demonstrated that mitochondrial activation, by the agonists of peroxisome proliferator-activated receptor g (PPARg) coactivator 1-alpha (PGC-1 alpha)/transcription factor complexes, had synergistic effects with a PD-1-blocking monoclonal antibody in a mouse tumor model. In the current study, we examined the molecular mechanismof the synergistic effects of bezafibrate, an agonist of PGC-1 alpha/PPAR complexes, which enhanced the tumoricidal effects of PD-1 blockade. Bezafibrate activated CTL mitochondria and upregulated oxidative phosphorylation as well as glycolysis, resulting in more proliferation of naive T cells and improved effector function in CTLs. Bezafibrate also increased fatty acid oxidation (FAO) and mitochondrial respiratory capacity, which supports the extra energy demands of cells in emergencies, allowing cell survival. Carnitine palmitoyl transferase 1 (Cpt1), which is needed for FAO, and Bcl2 were both upregulated. Cpt1 and Bcl2 can forma complex to prevent apoptosis of CTLs. Together, these results indicate that bezafibrate increases or maintains the number of functional CTLs by activating mitochondrial and cellular metabolism, leading in turn to enhanced antitumor immunity during PD-1 blockade. (C) 2018 AACR.
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