The mitochondrial pyruvate carrier regulates antitumor function and memory T cell differentiation

Effector CD8+ T cells engage glycolysis for both lactate fermentation and pyruvate oxidation, the latter requiring the mitochondrial pyruvate carrier (MPC). How mitochondrial pyruvate metabolism impacts T cell function and fate, remains incompletely understood. We found that genetic deletion of MPC drives CD8+ T cell differentiation towards a memory phenotype. Metabolic flexibility induced by MPC inhibition in a nutrient-rich environment allowed for increased acetyl-coenzyme-A production by glutamine and fatty acid oxidation. This correlated with histone acetylation and chromatin accessibility on pro-memory genes. However, in a nutrient-deprived tumor microenvironment, MPC is essential for sustaining lactate oxidation that limits the metabolic suppression of CD8+ T cell anti-tumor function. To optimally translate these findings, we used a small molecule MPC inhibitor to imprint a stable memory phenotype during chimeric antigen receptor (CAR) T manufacturing, and demonstrated that infusing metabolically conditioned MPC WT CAR T cells resulted in superior and long-lasting anti-tumor activity. Overall design: We performed a chromatin accessibility analysis by ATAC sequencing on CD8+ T cells that were activated for 3 days in the presence of DMSO or 75 micromolar UK5099 (a mitochondrial pyruvate carrier (MPC) inhibitor) and then cultured for an additional 4 days without MPC inhibition to identify the genomic regions that acquired a stable open conformation, at least over the course of several cell divisions, upon metabolic intervention.