1876PD - Immunogenicity of BRCA1-deficient ovarian cancers is driven through DNA sensing and is augmented by PARP inhibition

Abstract

BackgroundBRCA1 is an essential gene of the homologous recombination repair pathway. Ovarian cancers with BRCA1 mutations represent about 20% of HGSOC and are characterized by loss-of-function TP53 mutations, copy number alterations, chromosomal instability, high neoantigen loads and increased infiltration of intraepithelial CD8 tumor-infiltrating lymphocytes. MethodsTo address this hypothesis, we investigated the effects of BRCA1 loss on tumor immunogenicity in human and mouse ovarian cancer BRCA1 isogenic cell lines. We further studied tumor immunogenicity and immune recognition in situ in human ovarian carcinomas and in vivo using syngeneic transplantable Tp53-/-BrcaWT and Tp53-/-Brca1-/- mouse models. ResultsWe propose that DNA damage induced by BRCA1 loss could be a tumor-autonomous inflammatory mechanism. Our hypothesis was corroborated by studies in human and mouse isogenic ovarian cancer cell lines which revealed that BRCA1 deficiency leads to increased cytoplasmic translocation of nuclear DNA, increased DNA sensing, induction of proinflammatory cytokines and T cell recruiting chemokines and increased tumor CD8 T cell infiltration. PARP inhibition exacerbated type I IFN responses in BRCA1-deficient ovarian cancer cell lines and simultaneously increased surface expression of PDL1. Increased DNA damage, as measured by γH2AX tumor staining, was also detected in situ in human ovarian cancers with BRCA1 mutations. Importantly, we detected tumor expression of pSTAT1 confirming a type I IFN activation in tumors with DNA damage. Both DNA damage and pSTAT1 activation correlated with higher TIL infiltration and better overall survival. Our results translated in mouse models of ovarian cancer where Trp53-/-Brca1-/- but not Trp53-/-Brca1WT tumors presented with biomarkers of DNA damage, type I IFN pathway activation and responded to a therapeutic combination of PARP inhibitor Olaparib with dual checkpoint blockade antibodies. ConclusionsOur results provide a mechanistic link between loss of BRCA1 and induction of tumor-driven inflammatory and immunogenic responses in ovarian cancer that was mediated by tumor-cell autonomous type I IFN signaling, which translated to increased immune surveillance by CD8 T cells. Legal entity responsible for the studyGeorge Coukos. FundingThis study was supported by the Ludwig Institute for Cancer Research and grants P50 CA083638 SPORE in Ovarian Cancer, the Emma Mouschamp Foundation, the Porphyrogenis Fundation and by a Stand Up To Cancer-Ovarian Cancer Research Fund Alliance-National Ovarian Cancer Coalition Dream Team Translational Cancer Research Grant (SU2C-AACRDT16- 15, to EMS). Stand Up To Cancer is a division of the Entertainment 2 Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. DisclosureAll authors have declared no conflicts of interest.