Bench to bedside and back again: PARP Inhibitors

11:00 am-12:30 pm

Room: Boisdale

Programme stream(s): Cancer discovery / underpinning research , Treatment
Programme session type(s): Parallel session

Chair: Yvette Drew, Northern Institute for Cancer Research
Chair: Chris Lord, Institute of Cancer Research
Speaker: Graeme Smith, Artios Pharma Ltd
Speaker: Constantia Pantelidou, Dana Farber Cancer Institute, Boston, USA
Speaker: Daniel Hübschmann, HI-STEM: The Heidelberg Institute for Stem Cell Technology and Experimental Medicine

Combinatorial clinical trials of PARP inhibitors with immunotherapies are ongoing, yet the immunomodulatory effects of PARP inhibition have been incompletely studied. 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/Cas9-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.