PARPi Triggers the STING-Dependent Immune Response and Enhances the Therapeutic Efficacy of Immune Checkpoint Blockade Independent of BRCAness

• Published in: Cancer research (Chicago, Ill.) Vol. 79; no. 2; pp. 311 - 319
• Main Authors: Shen, Jianfeng, Zhao, Wei, Ju, Zhenlin, Wang, Lulu, Peng, Yang, Labrie, Marilyne, Yap, Timothy A, Mills, Gordon B, Peng, Guang
• Format: Journal Article
• Language: English
• Published: United States 15.01.2019
• Subjects: Animals; Antibodies - immunology; Antibodies - pharmacology; Antineoplastic Combined Chemotherapy Protocols - immunology; Antineoplastic Combined Chemotherapy Protocols - pharmacology; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - immunology; Cell Line, Tumor; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; DNA - genetics; DNA - immunology; Drug Synergism; Female; Genes, BRCA1; Genes, BRCA2; Humans; Membrane Proteins - immunology; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - immunology; Poly(ADP-ribose) Polymerase Inhibitors - immunology; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Signal Transduction - drug effects; Signal Transduction - immunology
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-18-1003

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