| First Author | Bian Y | Year | 2020 |
| Journal | Nature | Volume | 585 |
| Issue | 7824 | Pages | 277-282 |
| PubMed ID | 32879489 | Mgi Jnum | J:296748 |
| Mgi Id | MGI:6468810 | Doi | 10.1038/s41586-020-2682-1 |
| Citation | Bian Y, et al. (2020) Cancer SLC43A2 alters T cell methionine metabolism and histone methylation. Nature 585(7824):277-282 |
| abstractText | 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. Moreover, methionine supplementation improved the expression of H3K79me2 and STAT5 in T cells, and this was accompanied by increased T cell immunity in tumour-bearing mice and patients with colon cancer. Clinically, tumour SLC43A2 correlated negatively with T cell histone methylation and functional gene signatures. Our results identify a mechanistic connection between methionine metabolism, histone patterns, and T cell immunity in the tumour microenvironment. Thus, cancer methionine consumption is an immune evasion mechanism, and targeting cancer methionine signalling may provide an immunotherapeutic approach. |
