Cancer SLC43A2 alters T cell methionine metabolism and histone methylation.

ABSTRACT: Abnormal epigenetic patterns correlate with effector T cell malfunction in tumours^1-4, but the cause of this link is unknown. Here we show that tumour cells disrupt methionine metabolism in CD8⁺ T cells, thereby lowering intracellular levels of methionine and the methyl donor S-adenosylmethionine (SAM) and resulting in loss of dimethylation at lysine 79 of histone H3 (H3K79me2). Loss of H3K79me2 led to low expression of STAT5 and impaired T cell immunity. Mechanistically, tumour cells avidly consumed methionine and outcompeted T cells for methionine by expressing high levels of the methionine transporter SLC43A2. Genetic and biochemical inhibition of tumour SLC43A2 restored H3K79me2 in T cells, thereby boosting spontaneous and checkpoint-induced tumour immunity. Moreo

SUBMITTER: Bian Y 

PROVIDER: S-EPMC7486248 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature