通过调节与蛋白质稳定相关的干扰素通路激活,HRS通过调节瘤免疫逃避来调节瘤免疫逃避
Wei Zhang1, Jiegang Yang1, Beike Wang1
1Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell reports
|November 10, 2023
概括
破坏肝细胞生长因子调节的氨酸激酶基质 (HRS) 抑制瘤生长,通过促进T细胞透,增强抗PD-1疗法. 这表明HRS是提高高瘤突变负担癌症的癌症免疫治疗的目标.
科学领域:
- 在瘤学瘤学.
- 免疫学 免疫学 免疫学
- 细胞生物学 细胞生物学
背景情况:
- 运输所需的内体分类复合体 (ESCRT) 通常会减弱瘤信号.
- 矛盾的是,ESCRT成员,包括肝细胞生长因子调节的氨酸激酶基质 (HRS),在瘤中被上调.
- 对于HRS在瘤免疫逃避中的确切作用尚不清楚.
研究的目的:
- 调查HRS在瘤生长和免疫逃避中的作用.
- 探索在癌症免疫治疗中准HRS的治疗潜力.
主要方法:
- 利用黑色素瘤和结肠癌小鼠模型与HRS破坏.
- 分析了蛋白质积累,内质网膜 (ER) 压力和I型干扰素通路激活.
- 评估了CD8+ T细胞透和对抗PD-1疗法的反应.
- 与瘤突变负担 (TMB) 和患者对PD-L1/PD-1阻塞的反应相关的HRS表达.
主要成果:
- HRS 干扰抑制了瘤生长,并增加了 CD8+ T 细胞的透.
- 通过IRE1α/XBP1.1,HRS切除诱导了错误折叠的蛋白质积累,ER压力和I型干扰素通路的激活.
- 在高TMB瘤中,HRS被上调,并与免疫治疗反应相关.
- 在小鼠模型中,HRS抑制使瘤对抗PD-1治疗敏感.
结论:
- 具有高TMB的瘤细胞可能通过HRS介导的机制逃避免疫监测.
- 向HRS可以提高抗PD-1免疫疗法的有效性,特别是在高TMB癌症中.
- HRS代表了改善癌症免疫治疗结果的有希望的治疗标.
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