PARP Inhibition Induces Synthetic Lethality and Adaptive Immunity in LKB1-Mutant Lung Cancer
PARP Inhibition Induces Synthetic Lethality and Adaptive Immunity in LKB1-Mutant Lung Cancer
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PARP 抑制可诱导 LKB1 突变型肺癌的合成致死性和适应性免疫
DOI：
10.1158/0008-5472.can-22-1740
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发表时间：
2023-02-15
期刊：
影响因子：
11.2
通讯作者：
Dong, Zhong-Yi
中科院分区：
文献类型：
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作者：
Long, Li -Li;Ma, Si-Cong;Dong, Zhong-Yi
在突变的非小细胞肺癌(NSCLC)中，肝激酶B1(LKB1)突变的非小细胞肺癌(NSCLC)同时存在突变负荷升高和肿瘤微环境(TME)的矛盾特征。这种悖论背后的分子基础和为这些历史上难以治疗的癌症量身定做的策略是缺乏的。在这里，通过绘制Kras/Lkb1驱动的肺癌与Kras/Lkb1驱动的基因工程小鼠模型的单细胞转录图谱，我们在Kras/Lkb1驱动的肿瘤中检测到肿瘤固有的IFNy信号受损，这解释了惰性免疫环境。机制分析表明，突变的LKB1导致DNA损伤修复过程中的缺陷和PARP1的异常激活。过度激活的PARP1通过物理上与STAT1的多(ADP-核糖基)相互作用和增强STAT1的多聚(ADP-核糖基)而减弱IFNy途径，损害其磷酸化和激活。取消PARP1驱动的程序在非小细胞肺癌中触发了基于LKB1突变介导的DNA修复缺陷的合成致死性，同时也恢复了磷酸化的STAT1，从而有利于免疫逻辑上的“热”TME。因此，抑制PARP1恢复了中断的IFNy信号，从而在多种LKB1缺陷的小鼠肿瘤模型中启动了与PD-1阻断协同的适应性免疫反应。总之，本研究揭示了DNA修复过程和适应性免疫反应之间未知的相互作用，为双重PARP1和PD-1抑制治疗LKB1突变NSCLC提供了分子基础。意义：靶向PARP通过触发DNA损伤和适应性免疫，发挥双重作用，克服LKB1丢失驱动的免疫治疗抵抗，为双重PARP和PD-1抑制治疗LKB1突变肺癌提供了理论基础。
Contradictory characteristics of elevated mutational burden and a "cold" tumor microenvironment (TME) coexist in liver kinase B1 (LKB1)-mutant non-small cell lung cancers (NSCLC). The molec-ular basis underlying this paradox and strategies tailored to these historically difficult to treat cancers are lacking. Here, by mapping the single-cell transcriptomic landscape of genetically engineered mouse models with Kras versus Kras/Lkb1-driven lung tumors, we detected impaired tumor-intrinsic IFNy signaling in Kras/Lkb1- driven tumors that explains the inert immune context. Mechanistic analysis showed that mutant LKB1 led to deficiency in the DNA damage repair process and abnormally activated PARP1. Hyper -activated PARP1 attenuated the IFNy pathway by physically inter-acting with and enhancing the poly(ADP-ribosyl)ation of STAT1, compromising its phosphorylation and activation. Abrogation of the PARP1-driven program triggered synthetic lethality in NSCLC on the basis of the LKB1 mutation-mediated DNA repair defect, while also restoring phosphorylated STAT1 to favor an immuno-logically "hot" TME. Accordingly, PARP1 inhibition restored the disrupted IFNy signaling and thus mounted an adaptive immune response to synergize with PD-1 blockade in multiple LKB1-deficient murine tumor models. Overall, this study reveals an unexplored interplay between the DNA repair process and adaptive immune response, providing a molecular basis for dual PARP1 and PD-1 inhibition in treating LKB1-mutant NSCLC.Significance: Targeting PARP exerts dual effects to overcome LKB1 loss-driven immunotherapy resistance through triggering DNA damage and adaptive immunity, providing a rationale for dual PARP and PD-1 inhibition in treating LKB1-mutant lung cancers.