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Cancer Discov. 2019 Jun;9(6):722-737. doi: 10.1158/2159-8290.CD-18-1218. Epub 2019 Apr 23.

PARP Inhibitor Efficacy Depends on CD8+ T-cell Recruitment via Intratumoral STING Pathway Activation in BRCA-Deficient Models of Triple-Negative Breast Cancer.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts.
2
Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
3
Department of Imaging, A.C. Camargo Cancer Center, São Paulo, Brazil.
4
Breast Tumor Immunology Laboratory, Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute, Boston, Massachusetts.
5
Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
6
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
7
Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Switzerland.
8
Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts. geoffrey_shapiro@dfci.harvard.edu.
9
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
#
Contributed equally

Abstract

Combinatorial clinical trials of PARP inhibitors with immunotherapies are ongoing, yet the immunomodulatory effects of PARP inhibition have been incompletely studied. Here, we sought to dissect the mechanisms underlying PARP inhibitor-induced changes in the tumor microenvironment of BRCA1-deficient triple-negative breast cancer (TNBC). We demonstrate that the PARP inhibitor olaparib induces CD8+ T-cell infiltration and activation in vivo, and that CD8+ T-cell depletion severely compromises antitumor efficacy. Olaparib-induced T-cell recruitment is mediated through activation of the cGAS/STING pathway in tumor cells with paracrine activation of dendritic cells and is more pronounced in HR-deficient compared with HR-proficient TNBC cells and in vivo models. CRISPR-mediated knockout of STING in cancer cells prevents proinflammatory signaling and is sufficient to abolish olaparib-induced T-cell infiltration in vivo. These findings elucidate an additional mechanism of action of PARP inhibitors and provide a rationale for combining PARP inhibition with immunotherapies for the treatment of TNBC. SIGNIFICANCE: This work demonstrates cross-talk between PARP inhibition and the tumor microenvironment related to STING/TBK1/IRF3 pathway activation in cancer cells that governs CD8+ T-cell recruitment and antitumor efficacy. The data provide insight into the mechanism of action of PARP inhibitors in BRCA-associated breast cancer.This article is highlighted in the In This Issue feature, p. 681.

PMID:
31015319
PMCID:
PMC6548644
[Available on 2020-06-01]
DOI:
10.1158/2159-8290.CD-18-1218

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