Cell Mol Immunol. .: co-auth.: group Fajas

 2020 Feb 13. doi: 10.1038/s41423-020-0365-3. [Epub ahead of print]

Enforced PGC-1α expression promotes CD8 T cell fitness, memory formation and antitumor immunity.

Dumauthioz N1,2Tschumi B1,2Wenes M1,2Marti B1,2Wang H2,3Franco F2,3Li W4,5Lopez-Mejia IC6Fajas L6Ho PC2,3Donda A1,2Romero P7,8Zhang L9,10,11,12.


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.


Anti-tumor immunity; CD8; Memory; Mitochondria; PGC-1α

PMID: 32055005