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

Regulatory T (T_reg) cells, although vital for immune homeostasis, also represent a major barrier to anti-cancer immunity, as the tumour microenvironment (TME) promotes the recruitment, differentiation and activity of these cells^1,2. Tumour cells show deregulated metabolism, leading to a metabolite-depleted, hypoxic and acidic TME³, which places infiltrating effector T cells in competition with the tumour for metabolites and impairs their function^4-6. At the same time, T_reg cells maintain a strong suppression of effector T cells within the TME^7,8. As previous studies suggested that T_reg cells possess a distinct metabolic profile from effector T cells^9-11, we hypothesized that the altered metabolic landscape of the TME and increased activity of intratumoral T_reg cells are linked. Here we show that T_reg cells display broad heterogeneity in their metabolism of glucose within normal and transformed tissues, and can engage an alternative metabolic pathway to maintain suppressive function and proliferation. Glucose uptake correlates with poorer suppressive function and long-term instability, and high-glucose conditions impair the function and stability of T_reg cells in vitro. T_reg cells instead upregulate pathways involved in the metabolism of the glycolytic by-product lactic acid. T_reg cells withstand high-lactate conditions, and treatment with lactate prevents the destabilizing effects of high-glucose conditions, generating intermediates necessary for proliferation. Deletion of MCT1-a lactate transporter-in T_reg cells reveals that lactate uptake is dispensable for the function of peripheral T_reg cells but required intratumorally, resulting in slowed tumour growth and an increased response to immunotherapy. Thus, T_reg cells are metabolically flexible: they can use 'alternative' metabolites in the TME to maintain their suppressive identity. Further, our results suggest that tumours avoid destruction by not only depriving effector T cells of nutrients, but also metabolically supporting regulatory populations.