Metabolic Support of Tumour-infiltrating Regulatory T Cells by Lactic Acid

Regulatory T (T) 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. Tumour cells show deregulated metabolism, leading to a metabolite-depleted, hypoxic and acidic TME, which places infiltrating effector T cells in competition with the tumour for metabolites and impairs their function. At the same time, T cells maintain a strong suppression of effector T cells within the TME. As previous studies suggested that T cells possess a distinct metabolic profile from effector T cells, we hypothesized that the altered metabolic landscape of the TME and increased activity of intratumoral T cells are linked. Here we show that T 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 cells in vitro. T cells instead upregulate pathways involved in the metabolism of the glycolytic by-product lactic acid. T 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 cells reveals that lactate uptake is dispensable for the function of peripheral T cells but required intratumorally, resulting in slowed tumour growth and an increased response to immunotherapy. Thus, T 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.