2. Academic Validation
  3. PARP Inhibition Elicits STING-Dependent Antitumor Immunity in Brca1-Deficient Ovarian Cancer

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

  • Cell Rep. 2018 Dec 11;25(11):2972-2980.e5. doi: 10.1016/j.celrep.2018.11.054.
Liya Ding 1,  Hye-Jung Kim 2,  Qiwei Wang 1,  Michael Kearns 3,  Tao Jiang 3,  Carolynn E Ohlson 3,  Ben B Li 1,  Shaozhen Xie 3,  Joyce F Liu 4,  Elizabeth H Stover 4,  Brooke E Howitt 5,  Roderick T Bronson 5,  Suzan Lazo 2,  Thomas M Roberts 1,  Gordon J Freeman 4,  Panagiotis A Konstantinopoulos 6,  Ursula A Matulonis 7,  Jean J Zhao 8
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 2 Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 5 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 6 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: panagiotis_konstantinopoulos@dfci.harvard.edu.
  • 7 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: ursula_matulonis@dfci.harvard.edu.
  • 8 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: jean_zhao@dfci.harvard.edu.
PMID: 30540933 DOI: 10.1016/j.celrep.2018.11.054
Abstract

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

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

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