Extracellular-acidosis restricts one-carbon metabolism and preserves T cell stemness: RNA-seq

The accumulation of acidic metabolic waste products within the tumor microenvironment profoundly inhibits effector functions of tumor-infiltrating lymphocytes (TILs). However, it is unclear whether extracellular-acidosis impacts T cell metabolic fitness and differentiation status. Here, we surprisingly found that prolonged acid exposure reprogrammed T cell intracellular metabolism and mitochondrial fitness, and preserved T cell stemness. Elevated extracellular-acidosis impaired methionine uptake and metabolism via downregulating SLC7A5, therefore altering H3K27me3 deposition at the promoters of crucial T cell stemness genes. These changes promoted the maintenance of a “stem-like memory” state and improved long-term in vivo persistence and anti-tumor efficacy. Our findings not only reveal the unexpected roles of extracellular-acidosis in the maintenance of stem-like properties of T cells, but also advance our understanding of the direct involvement of methionine metabolism in T cell stemness. Overall design: Comparative gene expression profiling analysis of RNA-seq data for control versus 10mM lactic acid or pH6.6 conditioned human T cells.