Cancer SLC43A2 alters T cell methionine metabolism and histone methylation.

Abstract

Abnormal epigenetic patterns correlate with effector T cell malfunction in tumors1–4. However, their causal link is unknown. Here, we show that tumor cells disrupt methionine metabolism in CD8+ T cells, thereby lowering intracellular methionine levels and the methyl donor S-adenosylmethionine (SAM), resulting in loss of H3K79me2. Consequently, loss of H3K79me2 led to low STAT5 expression and impaired T cell immunity. Mechanistically, tumor cells avidly consumed and outcompeted T cells for methionine via high expression of SLC43A2, a methionine transporter. Genetic and biochemical inhibition of tumor SLC43A2 rescued T cell H3K79me2 levels, boosting spontaneous and checkpoint-induced tumor immunity. Moreover, we found that methionine supplementation improved expression of H3K79me2 and STAT5 in T cells, accompanied by increased T cell immunity in tumor bearing models and colon cancer patients. Clinically, tumor SLC43A2 negatively correlated with T cell histone methylation and functional gene signatures. Our work reveals a novel mechanistic connection between methionine metabolism, histone patterns, and T cell immunity in the tumor microenvironment. Thus, cancer methionine consumption is an unappreciated immune evasion mechanism, and targeting cancer methionine signaling may provide an immunotherapeutic approach.