Journal
CELL METABOLISM
Volume 34, Issue 8, Pages 1137-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2022.06.008
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This study reveals the mechanism by which tumor-derived lactate in the tumor microenvironment inhibits the cytotoxicity of CD8(+) T cells, highlighting the role of metabolic pathways in regulating T cell cytotoxicity.
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.
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