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

Area of Science:

• Immunology
• Oncology
• Metabolic pathways

Background:

• Succinate dehydrogenase (SDH) mutations cause succinate buildup in tumors, affecting immune cells.
• The impact of succinate on T cell function remains largely uninvestigated.

Purpose of the Study:

• To investigate the effects of tumor-associated succinate on human CD4+ and CD8+ T cells.
• To elucidate the mechanisms by which succinate influences T cell responses.
• To explore therapeutic strategies for restoring T cell function in SDH-deficient tumors.

Main Methods:

• Exposure of human CD4+ and CD8+ T cells to tumor-associated succinate concentrations.
• Analysis of T cell degranulation and cytokine secretion (e.g., IFN-γ).
• Investigation of succinate uptake mechanisms (e.g., MCT1) and metabolic effects.
• Assessment of interventions to restore glucose oxidation.
• Analysis of tumor RNA-sequencing data from pheochromocytoma (PC) and paraganglioma (PG) patients.

Main Results:

• Succinate suppresses T cell degranulation and secretion of anti-tumor cytokines like interferon-γ (IFN-γ).
• Succinate uptake via MCT1 inhibits succinyl coenzyme A synthetase and impairs the tricarboxylic acid cycle.
• Pharmacological and genetic interventions that restore glucose oxidation rescue T cell function.
• SDH-deficient PC and PG tumors show suppressed IFN-γ-induced gene expression compared to other tumor types.

Conclusions:

• Tumor-associated succinate accumulation impairs T cell anti-tumor immunity by disrupting cellular metabolism.
• Targeting metabolic pathways or restoring glucose oxidation may enhance anti-tumor T cell responses in SDH-deficient cancers.
• Succinate plays a significant role in modulating the tumor immune microenvironment in vivo.