癌症 SLC43A2 改变T细胞的甲基因代谢和组织蛋白甲基化
Yingjie Bian1,2, Wei Li1,2, Daniel M Kremer3
1Department of Surgery, University of Michigan School of Medicine, Ann Arbor, MI, USA.
Nature
|September 4, 2020
概括
瘤细胞通过消耗 metionin,耗尽 S-adenosylmethionine (SAM) 和降低基因组甲基化 (H3K79me2) 来破坏T细胞免疫力. 恢复氨酸水平或阻断瘤氨酸吸收可以增强抗瘤T细胞的反应.
科学领域:
- 免疫学
- 表观遗传学
- 代谢途径
背景情况:
- 异常的表观遗传模式与瘤中的T细胞功能障碍有关.
- 连接瘤微环境中的表观遗传变化和T细胞功能障碍的潜在机制尚不清楚.
研究的目的:
- 阐明瘤细胞氨酸代谢与CD8+ T细胞表观调节失调之间的机制联系.
- 研究瘤介导的甲素消耗对T细胞功能和抗瘤免疫力的影响.
主要方法:
- 在瘤微环境中的CD8+T细胞中分析氨酸代谢.
- 在T细胞中评估基因组甲基化模式 (H3K79me2) 和STAT5表达.
- 基因和生化抑制瘤氨酸载体SLC43A2.
- 在临床前模型和人类癌症患者中进行的氨酸补充研究.
主要成果:
- 瘤细胞热衷于消耗甲,降低CD8+T细胞中的细胞内含量和S- 腺甲 (SAM).
- 这导致H3K79me2减少,STAT5表达受损,T细胞免疫受损.
- 抑制瘤SLC43A2或补充 metionin恢复了H3K79me2,增强了STAT5,并增强了抗瘤免疫力.
- 瘤SLC43A2表达与T细胞基因甲基化和免疫基因特征相反相关.
结论:
- 瘤的氨酸消耗是一种破坏T细胞表观遗传调节的免疫规避策略.
- 向瘤氨酸代谢,特别是通过SLC43A2,是一种潜在的免疫治疗方法来增强抗瘤免疫力.
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