通过肺癌的综合应激反应途径对多个免疫检查点的协调转化控制
Shayna Thomas-Jardin1, Shruthy Suresh1,2,3, Ariana Arce1
1Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA.
bioRxiv : the preprint server for biology
|November 18, 2024
概括
综合应激反应 (ISR) 途径通过上调PD-L1和CD155.5来促进癌症免疫逃避. 抑制ISR可以增强抗癌免疫力,为肺癌提供新的治疗策略.
科学领域:
- 癌症免疫学 癌症免疫学
- 分子生物学分子生物学
- 瘤微环境是一个微环境.
背景情况:
- 综合应激反应 (ISR) 对于癌细胞在压力下生存至关重要.
- ISR激活导致编程死亡干1 (PD-L1) 诱导,抑制抗瘤免疫力.
- 瘤免疫逃生机制涉及多个免疫检查点蛋白.
研究的目的:
- 为了识别由ISR调节的额外免疫检查点蛋白质.
- 为了阐明ISR介导的瘤免疫逃生机制.
- 探索肺癌的新型治疗策略.
主要方法:
- 分析ISR调节的基因表达和蛋白质翻译.
- 调查上游开放阅读框架 (uORF) 在5' UTRs中的作用.
- 在人类初级肺瘤中对PD-L1和CD155表达的相关分析.
- 在临床前模型中评估联合PD-1阻断和ISR抑制 (ISRIB) 的疗效.
主要成果:
- 该ISR协调诱导PD-L1和CD155的表达.
- 通过绕过抑制性uORFs,ISR激活增强了PD-L1和CD155的翻译.
- 在人类肺瘤中观察到PD-L1和CD155表达之间的显著相关性.
- 激活ISR加速瘤发生,并损害T细胞功能.
- 结合PD-1阻断和ISR抑制可以克服这些影响.
结论:
- 该ISR代表了一种用于协调免疫检查点蛋白表达的新型调节机制.
- 在肺癌中,ISR通路是治疗的弱点.
- 将PD-1阻断与ISR抑制相结合,为肺癌患者提供了一个有希望的新疗法策略.
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