Pentose phosphate pathway activity regulates TCF1+ progenitor CD8+ T cells to improve immunotherapy 4810

Description TCF1high progenitor CD8+ T cells mediate the efficacy of immunotherapy; however, the mechanisms that govern their generation and maintenance are poorly understood. We demonstrate that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1high progenitor-exhausted-like phenotype and increased responsiveness to PD-1 blockade in vivo. PKM2KO CD8+ T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites and increased PPP cycling. Small molecule agonism of the PPP did not induce acute glycolytic impairment, but resulted in progressive alterations in glucose metabolism as demonstrated by 13C glucose carbon tracing. PPP agonism skewed CD8+ T cells toward a TCF1high population; intriguingly, PPP inhibition similarly induced a TCF1high population, however the transcriptional landscape of these progenitor populations were distinct between each other and compared with naturally arising TCF1high populations or those induced by glycolytic blockade. Finally, adoptive transfer of agonist-treated CD8+ T cells enhanced tumor control in combination with PD-1 blockade. Our findings demonstrate a critical importance for PPP activity regulating T cell differentiation and heterogeneity in the TCF1high progenitor state which can be leveraged to promote immunotherapy efficacy. Funding Sources Supported by: National Cancer Institute T32 CA203702, and the National Center for Advancing Translational Sciences of the National Institutes of Health under award numbers KL2-TR-002385 and 1R03TR004611-01A1. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)