Cell Reports
Volume 25, Issue 11, 11 December 2018, Pages 2972-2980.e5
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Report
PARP Inhibition Elicits STING-Dependent Antitumor Immunity in Brca1-Deficient Ovarian Cancer

https://doi.org/10.1016/j.celrep.2018.11.054Get rights and content
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Highlights

  • 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

Summary

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.

Keywords

PARP inhibition
BRCA deficiency
STING
immune response
PD-1 blockade
ovarian cancer
targeted therapy
immunotherapy
GEMM

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7

These authors contributed equally

8

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