Succinate uptake by T cells suppresses their effector function via inhibition of mitochondrial glucose oxidation.

ABSTRACT: Succinate dehydrogenase (SDH) loss-of-function mutations drive succinate accumulation in tumor microenvironments, for example in the neuroendocrine tumors pheochromocytoma (PC) and paraganglioma (PG). Control of innate immune cell activity by succinate is described, but effects on T cells have not been interrogated. Here we report that exposure of human CD4⁺ and CD8⁺ T cells to tumor-associated succinate concentrations suppresses degranulation and cytokine secretion, including of the key anti-tumor cytokine interferon-γ (IFN-γ). Mechanistically, this is associated with succinate uptake-partly via the monocarboxylate transporter 1 (MCT1)-inhibition of succinyl coenzyme A synthetase activity and impaired glucose flux through the tricarboxylic acid cycle. Consistently, p

SUBMITTER: Gudgeon N 

PROVIDER: S-EPMC9638018 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature