Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8⁺ T cells.

ABSTRACT: The tumor microenvironment (TME) is a unique metabolic niche that can inhibit T cell metabolism and cytotoxicity. To dissect the metabolic interplay between tumors and T cells, we establish an in vitro system that recapitulates the metabolic niche of the TME and allows us to define cell-specific metabolism. We identify tumor-derived lactate as an inhibitor of CD8⁺ T cell cytotoxicity, revealing an unexpected metabolic shunt in the TCA cycle. Metabolically fit cytotoxic T cells shunt succinate out of the TCA cycle to promote autocrine signaling via the succinate receptor (SUCNR1). Cytotoxic T cells are reliant on pyruvate carboxylase (PC) to replenish TCA cycle intermediates. By contrast, lactate reduces PC-mediated anaplerosis. The inhibition of pyruvate dehydrogenase (PDH) is sufficient to restore PC activity, succinate secretion, and the activation of SUCNR1. These studies identify PDH as a potential drug target to allow CD8⁺ T cells to retain cytotoxicity and overcome a lactate-enriched TME.

SUBMITTER: Elia I 

PROVIDER: S-EPMC9357162 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature