PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer
PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer
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DOI：
10.1172/jci123319
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发表时间：
2019-03-01
影响因子：
15.9
通讯作者：
Postel-Vinay, Sophie
中科院分区：
文献类型：
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作者：
Chabanon, Roman M.;Muirhead, Gareth;Postel-Vinay, Sophie
环GMP-AMP合酶/IFN基因刺激物（cGAS/STING）途径检测胞质DNA以激活先天性免疫应答。聚（ADP-核糖）聚合酶抑制剂（PARPi）选择性靶向具有DNA修复缺陷的癌细胞，例如由BRCA 1突变或ERCC 1缺陷引起的癌细胞。使用同基因细胞系和患者来源的样本，我们发现ERCC 1缺陷的非小细胞肺癌（NSCLC）细胞表现出增强的I型IFN转录组学特征，ERCC 1低表达与淋巴细胞浸润增加相关。我们证明了临床PARPi，包括奥拉帕尼和rucaparib，在ERCC 1缺陷型NSCLC和BRCA 1缺陷型三阴性乳腺癌（TNBC）细胞中具有细胞自主免疫调节特性。从机制上讲，PARPi产生具有微核特征的细胞质染色质片段;发现这些片段激活cGAS/STING、下游I型IFN信号传导和CCL 5分泌。重要的是，这些作用在PARP 1缺失的TNBC细胞中受到抑制，表明这种表型是PARPi对PARP 1的靶向作用所致。PARPi还增强了IFN-γ诱导的NSCLC细胞系和新鲜患者肿瘤细胞中的PD-L1表达;这种作用在ERCC 1缺陷的情况下增强。我们的数据为在适当分子选择的人群中使用PARPi作为免疫调节剂提供了临床前依据。
The cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway detects cytosolic DNA to activate innate immune responses. Poly(ADP-ribose) polymerase inhibitors (PARPi) selectively target cancer cells with DNA repair deficiencies such as those caused by BRCA1 mutations or ERCC1 defects. Using isogenic cell lines and patient-derived samples, we showed that ERCC1-defective non-small cell lung cancer (NSCLC) cells exhibit an enhanced type I IFN transcriptomic signature and that low ERCC1 expression correlates with increased lymphocytic infiltration. We demonstrated that clinical PARPi, including olaparib and rucaparib, have cell-autonomous immunomodulatory properties in ERCC1-defective NSCLC and BRCA1-defective triple-negative breast cancer (TNBC) cells. Mechanistically, PARPi generated cytoplasmic chromatin fragments with characteristics of micronuclei; these were found to activate cGAS/STING, downstream type I IFN signaling, and CCL5 secretion. Importantly, these effects were suppressed in PARP1-null TNBC cells, suggesting that this phenotype resulted from an on-target effect of PARPi on PARP1. PARPi also potentiated IFN-gamma-induced PD-L1 expression in NSCLC cell lines and in fresh patient tumor cells; this effect was enhanced in ERCC1-deficient contexts. Our data provide a preclinical rationale for using PARPi as immunomodulatory agents in appropriately molecularly selected populations.