Journal
CELLULAR & MOLECULAR IMMUNOLOGY
Volume 18, Issue 7, Pages 1761-1771Publisher
CHIN SOCIETY IMMUNOLOGY
DOI: 10.1038/s41423-020-0365-3
Keywords
PGC-1 alpha; Mitochondria; CD8; Memory; Anti-tumor immunity
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Funding
- Swiss National Science Foundation [PZ00P3_168077]
- SNSF [31003A_163204, 31003A_182470]
- CRI-CLIP award
- SNSF grant Sinergia [CRSII3_141879, CRSII3_160708]
- Foundation MEDIC
- Natural Science Foundation of China [NSFC 81971466, NSFC 31900645]
- Chinese Academy of Medical Sciences [2016-I2M-1-005]
- Swiss National Science Foundation (SNF) [CRSII3_160708, PZ00P3_168077, CRSII3_141879] Funding Source: Swiss National Science Foundation (SNF)
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The overexpression of PGC-1 alpha favors central memory formation of CD8 T cells and enhances antitumor immunity. CD8 T cells with enhanced PGC-1 alpha expression show stronger antitumor immunity in a melanoma model.
Memory CD8 T cells can provide long-term protection against tumors, which depends on their enhanced proliferative capacity, self-renewal and unique metabolic rewiring to sustain cellular fitness. Specifically, memory CD8 T cells engage oxidative phosphorylation and fatty acid oxidation to fulfill their metabolic demands. In contrast, tumor-infiltrating lymphocytes (TILs) display severe metabolic defects, which may underlie their functional decline. Here, we show that overexpression of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha), the master regulator of mitochondrial biogenesis (MB), favors CD8 T cell central memory formation rather than resident memory generation. PGC-1 alpha-overexpressing CD8 T cells persist and mediate more robust recall responses to bacterial infection or peptide vaccination. Importantly, CD8 T cells with enhanced PGC-1 alpha expression provide stronger antitumor immunity in a mouse melanoma model. Moreover, TILs overexpressing PGC-1 alpha maintain higher mitochondrial activity and improved expansion when rechallenged in a tumor-free host. Altogether, our findings indicate that enforcing mitochondrial biogenesis promotes CD8 T cell memory formation, metabolic fitness, and antitumor immunity in vivo.
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