@article {1656927,
	title = {Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8 T~cells},
	journal = {Cell Metab},
	volume = {34},
	number = {8},
	year = {2022},
	month = {2022 08 02},
	pages = {1137-1150.e6},
	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.},
	keywords = {CD8-Positive T-Lymphocytes, Humans, Immunity, Lactic Acid, Neoplasms, Pyruvate Carboxylase, Pyruvic Acid, Succinic Acid, Tumor Microenvironment},
	issn = {1932-7420},
	doi = {10.1016/j.cmet.2022.06.008},
	author = {Elia, Ilaria and Rowe, Jared H and Johnson, Sheila and Joshi, Shakchhi and Notarangelo, Giulia and Kurmi, Kiran and Weiss, Sarah and Freeman, Gordon J and Sharpe, Arlene H and Haigis, Marcia C}
}
