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Gudgeon, Nancy; Munford, Haydn; Bishop, Emma L.; Hill, James; Fulton-Ward, Taylor; Bending, David; Roberts, Jennie; Tennant, Daniel A.; Dimeloe, Sarah
Cell reports, 08/2022, Letnik: 40, Številka: 7Journal Article
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, pharmacological and genetic interventions restoring glucose oxidation rescue T cell function. Tumor RNA-sequencing data from patients with PC and PG reveal profound suppression of IFN-γ-induced genes in SDH-deficient tumors compared with those with other mutations, supporting a role for succinate in modulating the anti-tumor immune response in vivo. Display omitted •Succinate inhibits CD4+ and CD8+ T cell effector function, including IFN-γ secretion•T cells readily assimilate succinate from their environment•Succinate inhibits T cell succinyl-CoA synthetase activity and the TCA cycle•Neuroendocrine tumors with succinate dehydrogenase mutations have poor IFN-γ responses Succinate dehydrogenase (SDH) mutations drive succinate accumulation in tumor microenvironments. Gudgeon et al. observe that succinate suppresses T cell degranulation and cytokine secretion, particularly IFN-γ. This is associated with succinate uptake, inhibited succinyl-CoA synthetase activity, and impaired tricarboxylic acid cycle flux. Consistently, IFN-γ-induced genes are suppressed in SDH-deficient neuroendocrine tumors.
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