PARPI triggers the STING-dependent immune response and enhances the therapeutic efficacy of immune checkpoint blockade independent of BRCANEss

Jianfeng Shen, Wei Zhao, Zhenlin Ju, Lulu Wang, Yang Peng, Marilyne Labrie, Timothy A. Yap, Gordon B. Mills, Guang Peng

    Research output: Contribution to journalArticlepeer-review

    82 Scopus citations

    Abstract

    PARP inhibitors (PARPi) have shown remarkable therapeu-way and stimulated production of type I IFNs to induce tic efficacy against BRCA1/2-mutant cancers through a syn-antitumor immunity independent of BRCAness. These effects thetic lethal interaction. PARPi exert their therapeutic effects of PARPi were further enhanced by immune checkpoint mainly through the blockade of ssDNA damage repair, which blockade. Overall, these results provide a mechanistic ratio-leads to the accumulation of toxic DNA double-strand breaks nale for using PARPi as immunomodulatory agents to harness specifically in cancer cells with DNA repair deficiency (BCRA-the therapeutic efficacy of immune checkpoint blockade. ness), including those harboring BRCA1/2 mutations. Here we show that PARPi-mediated modulation of the immune Significance: This work uncovers the mechanism behind response contributes to their therapeutic effects independently the clinical efficacy of PARPi in patients with both BRCA-of BRCA1/2 mutations. PARPi promoted accumulation of wild-type and BRCA-mutant tumors and provides a ratio-cytosolic DNA fragments because of unresolved DNA lesions, nale for combining PARPi with immunotherapy in patients which in turn activated the DNA-sensing cGAS–STING path-with cancer.

    Original languageEnglish (US)
    Pages (from-to)311-319
    Number of pages9
    JournalCancer Research
    Volume79
    Issue number2
    DOIs
    StatePublished - Jan 15 2019

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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