ARIH1激活STING介导的T细胞激活,并使瘤对免疫检查点阻塞产生敏感性
Xiaolan Liu1, Xufeng Cen2, Ronghai Wu3
1Department of Biochemistry & Research Center of Clinical Pharmacy of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Nature communications
|July 10, 2023
概括
西斯普拉丁和ACY738通过上调ARIH1,激活STING通路来增强癌症免疫疗法. 这种策略克服了对PD-L1阻塞的抗性,提高了治疗疗效.
科学领域:
- 在瘤学瘤学.
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
背景情况:
- 免疫检查点阻塞 (ICB) 在一些癌症患者中显示出有限的疗效,需要对抗性机制进行研究.
- 了解瘤如何逃避ICB治疗对于开发更有效的治疗方法至关重要.
研究的目的:
- 确定对PD-L1阻塞的抵抗机制,并发现增强ICB疗效的策略.
- 为了研究Ariadne RBR E3泛素蛋白联酶1 (ARIH1) 在ICB耐药性和反应中的作用.
主要方法:
- 利用ICB不敏感的瘤模型研究抗性机制.
- 研究了西斯丁和ACY738对PD-L1阻断功效和ARIH1表达的影响.
- 研究了ARIH1在T细胞透,瘤生长和STING通路激活中的作用.
- 进行高通量药物选,以识别ARIH1上调化合物.
主要成果:
- 西斯普拉丁通过上调ARIH1来增强PD-L1阻塞,促进细胞毒性T细胞透,并抑制瘤生长.
- ARIH1调解DNA-PKcs降解,激活STING通路,这对于抗瘤反应至关重要.
- 通过药物查识别的ACY738有效地调节ARIH1并激活STING信号,使瘤对PD-L1阻塞敏感.
结论:
- 瘤对ICB的耐药性可以通过ARIH1及其下游信号通路 (DNA-PKcs-STING) 的损失来调解.
- 激活ARIH1是克服ICB耐药性和改善癌症免疫治疗结果的有希望的策略.
- 针对ARIH1-STING轴提供了一种新的治疗方法,以提高抗PD-L1治疗疗效.
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