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外核酶TREX1构成一个天生的免疫检查点,限制cGAS/STING介导的抗瘤免疫力

Junghyun Lim¹, Ryan Rodriguez¹, Katherine Williams¹

¹Genentech Inc., South San Francisco, California.

Cancer immunology research

|March 15, 2024

概括

DNA外核酶TREX1可以防止瘤躲避免疫系统. 抑制TREX1可以增强抗瘤免疫力,并通过减少瘤DNA和激活免疫细胞来增强癌症治疗.

科学领域:

免疫学免疫学免疫学
分子生物学分子生物学
癌症研究癌症研究

背景情况:

DNA外核酶三大修复外核酶1 (TREX1) 降解细胞质DNA,通过cGAS/STING通路和I型干扰素 (IFN) 阻止自身免疫反应.
瘤细胞往往会积累细胞质DNA,可能触发免疫反应.

研究的目的:

调查TREX1在限制瘤免疫性和其作为治疗点的潜力的作用.

主要方法:

评估TREX1对瘤细胞中cGAS/STING通路的影响.
评估了TREX1缺乏对小鼠模型瘤生长的影响.
分析了TREX1-缺乏瘤中的免疫细胞激活,T细胞疲劳和骨髓区变化.
研究了TREX1抑制与免疫检查点阻塞的组合.

主要成果:

瘤细胞中的TREX1缺乏限制了cGAS/STING激活和I型IFN反应,从而限制了小鼠的瘤生长.
在TREX1缺乏的小鼠中,减少瘤生长需要功能性免疫系统,系统性I型IFN信号传递和瘤cGAS.
丢失TREX1促进了CD8+T细胞和NK细胞的激活,减少了T细胞的耗尽,并将骨髓区转向抗瘤表型.
将TREX1抑制与T细胞导向的免疫检查点阻塞结合起来显示出协同效应.

结论:

TREX1作为一个关键的检查点,通过抑制先天免疫路径来限制瘤免疫性.
向TREX1可以重塑瘤微环境,增强内源抗瘤免疫力,并与现有的免疫疗法协同作用.

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