PARP inhibitor efficacy depends on CD8+ T cell recruitment via intratumoral STING pathway activation in BRCA-deficient models of triple-negative breast cancer.

Pantelidou, Constantia; Sonzogni, Olmo; de Oliveira Taveira, Mateus; Mehta, Anita K; Kothari, Aditi; Wang, Dan; Visal, Tanvi; Li, Michelle K; Pinto, Jocelin; Castrillon, Jessica A; Cheney, Emily M; Bouwman, Peter; Jonkers, Jos; Rottenberg, Sven; Guerriero, Jennifer L; Wulf, Gerburg M; Shapiro, Geoffrey I (2019). PARP inhibitor efficacy depends on CD8+ T cell recruitment via intratumoral STING pathway activation in BRCA-deficient models of triple-negative breast cancer. Cancer discovery, 9(6), pp. 722-737. American Association for Cancer Research 10.1158/2159-8290.CD-18-1218

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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 anti-tumor 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 to HR-proficient TNBC cells and in vivo models. CRISPR-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 rationale for combining PARP inhibition with immunotherapies for the treatment of TNBC.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

Rottenberg, Sven

Subjects:

600 Technology > 630 Agriculture
500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

2159-8290

Publisher:

American Association for Cancer Research

Language:

English

Submitter:

Sven Rottenberg

Date Deposited:

05 Jun 2019 15:46

Last Modified:

06 Jun 2019 01:32

Publisher DOI:

10.1158/2159-8290.CD-18-1218

PubMed ID:

31015319

BORIS DOI:

10.7892/boris.130582

URI:

https://boris.unibe.ch/id/eprint/130582

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