瘤中的ADAR1损失克服了免疫检查点阻塞的抵抗力
Jeffrey J Ishizuka1,2,3, Robert T Manguso1,3, Collins K Cheruiyot1,3
1Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
瘤细胞中的RNA编辑酶ADAR1的损失使其对免疫疗法敏感,并通过增加炎症来克服对检查点阻塞的抵抗. 在某些癌症中,这种策略可能会绕过T细胞识别的需要.
科学领域:
- 免疫学
- 癌症学
- 分子生物学
背景情况:
- 许多癌症患者对免疫检查点阻塞 (ICB) 没有反应或产生耐药性.
- 由于获得突变而导致的抗原表达受损是ICB耐药性的常见原因.
- 在调节细胞对免疫刺激的反应中,RNA编辑起着至关重要的作用.
研究的目的:
- 研究RNA编辑酶ADAR1在瘤对免疫疗法的反应中的作用.
- 确定ADAR1功能丧失是否可以克服对ICB的抗性.
- 阐明ADAR1影响抗瘤免疫力的机制.
主要方法:
- 研究了ADAR1功能丧失对瘤细胞的影响.
- 分析了干扰素诱导RNA的A-to-I编辑水平.
- 研究了PKR和MDA5通路的激活.
- 评估瘤对PD-1检查点的敏感性.
主要成果:
- ADAR1功能丧失使瘤对免疫疗法产生极大的敏感性.
- 减少ADAR1活动导致干扰素诱导RNA的A-to-I编辑减少.
- 这导致PKR和MDA5的激活,促进瘤生长抑制和炎症.
- 由于抗原呈现受损,ADAR1的丧失克服了PD-1阻抗.
结论:
- 在抗瘤免疫中,ADAR1充当抑制检查点,限制先天的连接体感应.
- 向ADAR1可以使瘤对免疫疗法敏感并克服耐药性.
- 通过ADAR1抑制诱导炎症可能会绕过 CD8+ T 细胞识别的需要,从而提供针对免疫疗法耐药性的总体策略.
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