Cell-autonomous inflammation of BRCA1-deficient ovarian cancers drives both tumor-intrinsic immunoreactivity and immune resistance through STING

Abstract

We investigated mechanisms leading to inflammation and immunoreactivity in ovarian tumors with homologous recombination deficiency. BRCA1lossis found to lead to transcriptional reprogramming in tumor cells and cell-intrinsic inflammation involving type I IFN and STING.BRCA1-mutated (BRCA1mut) tumors are thus T-cell inflamed at baseline. Genetic deletion or methylation of DNA-sensing/IFN genes or CCL5chemokineare identified as potential mechanism to attenuate T cell inflammation. Alternatively, in BRCA1mutcancersretaining inflammation, STING up regulates VEGF-A, mediating immune resistance and tumor progression. Tumor intrinsic STING elimination reduces neoangiogenesis, increasesCD8+T cell infiltration and reverts therapeutic resistance to dual immune checkpoint blockade(ICB). VEGF-A blockade phenocopies genetic STING loss and synergizes with IC Band/or PARP inhibitors to control the outgrowth of Trp53-/-Brca1-/-but notBrca1+/+ovarian tumors in vivo, offering rational combinatorial therapies for HRD cancers