Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Nature. 2020 Sep;585(7824):277-282. doi: 10.1038/s41586-020-2682-1. Epub 2020 Sep 2.
Abnormal epigenetic patterns correlate with effector T cell malfunction in tumours, 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.
异常的表观遗传模式与肿瘤中效应 T 细胞功能障碍相关，但这种联系的原因尚不清楚。在这里，我们表明肿瘤细胞会破坏 CD8 T 细胞中的蛋氨酸代谢，从而降低细胞内蛋氨酸和甲基供体 S-腺苷甲硫氨酸（SAM）的水平，导致组蛋白 H3 赖氨酸 79 上的二甲基化（H3K79me2）丢失。H3K79me2 的丢失导致 STAT5 表达降低，并损害 T 细胞免疫。从机制上讲，肿瘤细胞通过表达高水平的蛋氨酸转运蛋白 SLC43A2 来消耗蛋氨酸并与 T 细胞竞争蛋氨酸，从而大量消耗蛋氨酸。肿瘤 SLC43A2 的遗传和生化抑制恢复了 T 细胞中的 H3K79me2，从而增强了自发和检查点诱导的肿瘤免疫。此外，蛋氨酸补充提高了 T 细胞中 H3K79me2 和 STAT5 的表达，并且伴随着荷瘤小鼠和结肠癌患者 T 细胞免疫的增强。临床上，肿瘤 SLC43A2 与 T 细胞组蛋白甲基化和功能基因特征呈负相关。我们的研究结果确定了肿瘤微环境中蛋氨酸代谢、组蛋白模式和 T 细胞免疫之间的机制联系。因此，癌症对蛋氨酸的消耗是一种免疫逃避机制，而针对癌症蛋氨酸信号可能提供一种免疫治疗方法。
