癌症中的Y染色体损失通过逃避适应性免疫驱动生长
Hany A Abdel-Hafiz1, Johanna M Schafer2,3, Xingyu Chen1
1Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Nature
|June 21, 2023
概括
膀癌中Y染色体 (LOY) 的丧失与患者的病情恶化和瘤的攻击性增加有关. Y阴性瘤会损害T细胞的功能,使它们对PD-1免疫疗法产生更强的反应.
科学领域:
- 癌症学
- 遗传学
- 免疫学
背景情况:
- 在各种癌症中发现Y染色体 (LOY) 损失,其中包括10-40%的膀癌.
- 在癌症中LOY的临床和生物学意义仍然很大程度上是未知的.
研究的目的:
- 研究LOY在膀癌的临床和生物影响.
- 探索 LOY,瘤微环境和免疫疗法的反应之间的关系.
主要方法:
- 膀癌的基因组和转录组分析.
- 在LOY突变和CRISPR- Cas9Y删除膀癌细胞的体外研究.
- 在免疫能力强的宿主体内进行体内研究.
- 高维流细胞测量,单核RNA测序和空间蛋白质组评估.
主要成果:
- LOY与膀癌患者的预后不佳相关.
- 在具有免疫能力的宿主中,Y阴性瘤通过T细胞依赖机制表现出更强的攻击性.
- Y阴性瘤在瘤微环境中诱导CD8+T细胞功能障碍和疲劳.
- 抗PD-1 免疫检查点阻塞疗法对Y阴性瘤的反应增强.
结论:
- 具有LOY突变的癌细胞改变T细胞功能,导致T细胞衰竭.
- LOY状态可以作为预测PD-1向免疫疗法的生物标志物.
- 这项研究提供了LOY生物学及其对癌症免疫治疗策略的影响.
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