PARPi Triggers the STING-Dependent Immune Response and Enhances the Therapeutic Efficacy of Immune Checkpoint Blockade Independent of BRCAness
作者： Jianfeng Shen , Wei Zhao , Zhenlin Ju , Lulu Wang , Yang Peng
DOI: 10.1158/0008-5472.CAN-18-1003
关键词:
摘要: Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have shown remarkable therapeutic efficacy against BRCA1/2 mutant cancers through a synthetic lethal interaction. PARPi exert their effects mainly the blockade of single-stranded DNA damage repair, which leads to accumulation toxic double-strand breaks specifically in cancer cells with repair deficiency (BCRAness), including those harboring mutations. Here we show that PARPi-mediated modulation immune response contributes independently promoted cytosolic fragments due unresolved lesions, turn activated sensing cGAS-STING pathway and stimulated production type I interferons induce antitumor immunity independent BRCAness. These were further enhanced by checkpoint blockade. Overall, these results provide mechanistic rationale for using as immunomodulatory agents harness
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