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

Elia, I.; Rowe, J.H.; Johnson, S.; Joshi, S.; Notarangelo, G.; Kurmi, K.; Weiss, S.; Freeman, G.J.; Sharpe, A.H.; Haigis, M.C.; Elia, I; Rowe, J.H; Johnson, S; Joshi, S; Notarangelo, G; Kurmi, K; Weiss, S; Freeman, G.J; Sharpe, A.H; Haigis, M.C

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

Elia, I.; Rowe, J.H.; Johnson, S.; Joshi, S.; Notarangelo, G.; Kurmi, K.; Weiss, S.; Freeman, G.J.; Sharpe, A.H.; Haigis, M.C.

Cell Metabolism 34(8): 1137-1150.E6

2022

ISSN/ISBN: 1932-7420

PMID: 35820416

Accession: 080102481

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Summary

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.