PARP Inhibition Elicits STING-Dependent Antitumor Immunity in Brca1-Deficient Ovarian Cancer

• Published in: Cell reports (Cambridge) Vol. 25; no. 11; pp. 2972 - 2980.e5
• Main Authors: Ding, Liya, Kim, Hye-Jung, Wang, Qiwei, Kearns, Michael, Jiang, Tao, Ohlson, Carolynn E., Li, Ben B., Xie, Shaozhen, Liu, Joyce F., Stover, Elizabeth H., Howitt, Brooke E., Bronson, Roderick T., Lazo, Suzan, Roberts, Thomas M., Freeman, Gordon J., Konstantinopoulos, Panagiotis A., Matulonis, Ursula A., Zhao, Jean J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.12.2018; Elsevier
• Subjects: Animals; BRCA deficiency; BRCA1 Protein - deficiency; BRCA1 Protein - metabolism; Dendritic Cells - drug effects; Dendritic Cells - metabolism; Female; GEMM; HEK293 Cells; Humans; immune response; Immunity - drug effects; immunotherapy; Membrane Proteins - metabolism; Mice, Inbred C57BL; ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - immunology; Ovarian Neoplasms - pathology; PARP inhibition; PD-1 blockade; Phthalazines - pharmacology; Phthalazines - therapeutic use; Piperazines - pharmacology; Piperazines - therapeutic use; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Programmed Cell Death 1 Receptor - metabolism; STING; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - metabolism; targeted therapy; Treatment Outcome; targeted therapy; immune response; ovarian cancer; immunotherapy; PD-1 blockade; STING; PARP inhibition; BRCA deficiency; GEMM
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.11.054

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. [Display omitted] •T cell-mediated cytotoxicity is important for therapeutic activity of PARP inhibition•Olaparib-treated Brca1-deficient tumor cells activate the STING pathway in APCs•STING pathway activation is required for the antitumor efficacy of PARP inhibition•PD-1 blockade enhances the antitumor efficacy of olaparib in Brca1-deficient tumors Ding et al. show that PARP inhibition in Brca1-deficient tumors elicits strong antitumor immunity involving activation of both innate and adaptive immune responses, a process that is dependent on STING pathway activation. In addition, they show that addition of PD-1 blockade augments the therapeutic efficacy of PARP inhibitor treatment.