Metabolic support of tumour-infiltrating regulatory T cells by lactic acid.

Abstract

SUMMARYRegulatory T (Treg) cells, vital for maintaining immune homeostasis, also represent a major barrier to cancer immunity, as the tumor microenvironment (TME) promotes Treg cell recruitment, differentiation, and activity1,2. Tumor cells have deregulated metabolism leading to a metabolite-depleted, hypoxic, and acidic TME3, placing infiltrating effector T cells in competition with tumors for metabolites, impairing their function4–6. Conversely, Treg cells maintain high suppressive function within the TME7,8. As previous studies suggested Treg cells possess a distinct metabolic profile from effector T cells9–11, we hypothesized the altered metabolic landscape of the TME and increased activity of intratumoral Treg cells are linked. Here we show Treg 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 Treg cell function and stability. Treg cells rather upregulate pathways in metabolism of the glycolytic byproduct lactic acid. Treg cells withstood high lactate conditions, and lactate treatment prevented the destabilizing effects of high glucose, generating intermediates necessary for proliferation. Treg cell-restricted deletion of MCT1, a lactate transporter, revealed lactate uptake is dispensable for peripheral Treg cell function but required intratumorally, resulting in slowed tumor growth and increased response to immunotherapy. Thus Treg 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.