1. Enforced PGC-1α expression promotes CD8 T cell fitness, memory formation and antitumor immunity.
- Author
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Dumauthioz N, Tschumi B, Wenes M, Marti B, Wang H, Franco F, Li W, Lopez-Mejia IC, Fajas L, Ho PC, Donda A, Romero P, and Zhang L
- Subjects
- Animals, CD8-Positive T-Lymphocytes metabolism, Mice, Mitochondria metabolism, Organelle Biogenesis, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism, Vaccines, Subunit, Cancer Vaccines
- Abstract
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-1α), the master regulator of mitochondrial biogenesis (MB), favors CD8 T cell central memory formation rather than resident memory generation. PGC-1α-overexpressing CD8 T cells persist and mediate more robust recall responses to bacterial infection or peptide vaccination. Importantly, CD8 T cells with enhanced PGC-1α expression provide stronger antitumor immunity in a mouse melanoma model. Moreover, TILs overexpressing PGC-1α 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.
- Published
- 2021
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