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

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-1αexpression provide stronger antitumor immunity in a mouse melanoma model.Moreover,TILs overexpressing PGC-1αmaintain 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.