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

Nancy Gudgeon, Haydn Munford, Emma L Bishop, James Hill, Taylor Fulton-Ward, David Bending, Jennie Roberts, Daniel A Tennant, Sarah Dimeloe

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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, 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.

Original languageEnglish
Article number111193
JournalCell Reports
Volume40
Issue number7
DOIs
Publication statusPublished - 16 Aug 2022

Bibliographical note

Copyright © 2022 The Author(s).

Keywords

  • Adrenal Gland Neoplasms/genetics
  • CD8-Positive T-Lymphocytes
  • Cytokines
  • Glucose
  • Humans
  • Paraganglioma/genetics
  • Pheochromocytoma/genetics
  • Succinates
  • Succinic Acid
  • Tumor Microenvironment

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