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 depletion of CD8+ T cells severely compromises anti-tumor efficacy. Olaparib-induced T cell recruitment is mediated through activation of the STING/TBK1/IRF3 pathway in tumor and dendritic cells and is more pronounced in HR-deficient compared to HR-proficient TNBC cells. CRISPR-knockout of STING in cancer cells prevents type I IFN production and is sufficient to abolish PARP inhibitor-induced T cell infiltration in vivo. These findings elucidate a novel mechanism of action of PARP inhibitors and provide mechanistic rationale for combining PARP inhibition with immunotherapies for the treatment of TNBC.

Citation Format: Constantia Pantelidou, Olmo Sonzogni, Mateus De Oliveira Taveira, Anita K. Mehta, Dan Wang, Aditi Kothari, Michelle K. Li, Tanvi H. Visal, Jennifer L. Guerriero, Gerburg M. Wulf, Geoffrey I. Shapiro. PARP inhibitor efficacy depends on CD8+ T-cell recruitment via the STING pathway in BRCA-deficient models of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4490.