德诺沃表观遗传程序抑制PD-1阻断介导的T细胞复原
Hazem E Ghoneim1, Yiping Fan2, Ardiana Moustaki1
1Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Cell
|June 27, 2017
概括
阻断CD8T细胞中的DNA甲基化有助于它们对抗慢性感染和癌症. 在免疫检查点阻塞治疗期间,这种方法可以克服T细胞疲劳,改善免疫反应和瘤控制.
科学领域:
- 免疫学
- 表观遗传学
- 癌症生物学
背景情况:
- 免疫检查点阻断 (ICB) 能使耗尽的T细胞复原,
- 完全耗尽的T细胞抵抗了ICB,限制了治疗的疗效.
- 长期暴露于抗原会导致T细胞衰竭,阻碍免疫反应.
研究的目的:
- 研究新型DNA甲基化在T细胞衰竭中的作用.
- 确定阻断DNA甲基化是否可以在慢性刺激期间恢复T细胞功能.
- 评估ICB耐火T细胞中逆转DNA甲基化程序的治疗潜力.
主要方法:
- 在小鼠CD8T细胞上进行全基因组二硫酸盐测序 (WGBS).
- 在效应和耗尽阶段对DNA甲基化模式的分析.
- 在ICB和表观遗传调节后评估T细胞反应和瘤控制.
主要成果:
- 在耗尽的CD8T细胞中发现了渐进的,可遗传的de novo甲基化程序.
- 这些甲基化程序在PD-1封锁期间限制T细胞扩张和克隆多样性.
- 在透瘤的PD-1hi CD8 T细胞中观察到与疲劳相关的DNA甲基化.
- 这些甲基化程序的逆转增强了T细胞反应和瘤控制.
结论:
- 通过新的DNA甲基化程序, 调节T细胞的衰竭.
- DNA甲基化的表观遗传重新编程是ICB介导的T细胞复原的障碍.
- 针对DNA甲基化途径提供了一种克服T细胞衰竭和改善癌症免疫疗法的新方法.
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