Metabolic support of tumor-infiltrating regulatory T cells by lactic acid

SUMMARY

Regulatory T (T _reg) cells, vital for maintaining immune homeostasis, also represent a major barrier to cancer immunity, as the tumor microenvironment (TME) promotes T _reg cell recruitment, differentiation, and activity ^{1, 2} . Tumor cells have deregulated metabolism leading to a metabolite-depleted, hypoxic, and acidic TME ³ , placing infiltrating effector T cells in competition with tumors for metabolites, impairing their function ^{4– 6} . Conversely, T _reg cells maintain high suppressive function within the TME ^{7, 8} . As previous studies suggested T _reg cells possess a distinct metabolic profile from effector T cells ^{9– 11} , we hypothesized the altered metabolic landscape of the TME and increased activity of intratumoral T _reg cells are linked. Here we show T _reg cells display broad heterogeneity in utilization of glucose metabolism within normal and transformed tissues and can engage an alternative metabolic pathway to maintain suppressive function and proliferation. Glucose uptake correlated with poorer suppressive function and long-term instability, and high glucose culture impaired T _reg cell function and stability. T _reg cells rather upregulate pathways in metabolism of the glycolytic byproduct lactic acid. T _reg cells withstood high lactate conditions, and lactate treatment prevented the destabilizing effects of high glucose, generating intermediates necessary for proliferation. T _reg cell-restricted deletion of MCT1, a lactate transporter, revealed lactate uptake is dispensable for peripheral T _reg cell function but required intratumorally, resulting in slowed tumor growth and increased response to immunotherapy. Thus T _reg cells are metabolically flexible: they can utilize ‘alternative’ metabolites in the TME to maintain suppressive identity. Further, our studies suggest tumors avoid destruction by not only depriving effector T cells of nutrients, but also metabolically supporting regulatory populations.