PARP Inhibition Elicits STING-Dependent Antitumor Immunity in Brca1-Deficient Ovarian Cancer
PARP Inhibition Elicits STING-Dependent Antitumor Immunity in Brca1-Deficient Ovarian Cancer
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DOI：
10.1016/j.celrep.2018.11.054
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发表时间：
2018-12-11
期刊：
影响因子：
8.8
通讯作者：
Zhao, Jean J.
中科院分区：
文献类型：
--
作者：
Ding, Liya;Kim, Hye-Jung;Zhao, Jean J.
PARP抑制剂已显示出对BRCA突变患者的良好临床活性，并正在改变卵巢癌治疗的格局。然而，抑制PARP在肿瘤与肿瘤微环境和宿主免疫系统相互作用中的作用机制尚不清楚。我们发现，在BRCA1缺陷的卵巢肿瘤小鼠中，通过刺痛依赖的抗肿瘤免疫反应，奥拉帕利抑制PARP触发了强大的局部和系统抗肿瘤免疫，包括适应性和先天免疫反应。当奥拉帕利布与PD-1阻断剂联合使用时，这种作用进一步增强。我们的研究结果为抑制PARP发挥抗肿瘤作用提供了分子机制，并为改善癌症患者的治疗效果奠定了基础。
PARP inhibitors have shown promising clinical activities for patients with BRCA mutations and are changing the landscape of ovarian cancer treatment. However, the therapeutic mechanisms of action for PARP inhibition in the interaction of tumors with the tumor microenvironment and the host immune system remain unclear. We find that PARP inhibition by olaparib triggers robust local and systemic antitumor immunity involving both adaptive and innate immune responses through a STING-dependent antitumor immune response in mice bearing Brca1-deficient ovarian tumors. This effect is further augmented when olaparib is combined with PD-1 blockade. Our findings thus provide a molecular mechanism underlying antitumor activity by PARP inhibition and lay a foundation to improve therapeutic outcome for cancer patients.