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

In this study, we investigate mechanisms leading to inflammation and immunoreactivity in ovarian tumors with homologous recombination deficiency (HRD). BRCA1 loss is found to lead to transcriptional reprogramming in tumor cells and cell-intrinsic inflammation involving type I interferon (IFN) and stimulator of IFN genes (STING). BRCA1-mutated (BRCA1(mut)) tumors are thus T cell inflamed at baseline. Genetic deletion or methylation of DNA-sensing/IFN genes or CCL5 chemokine is identified as a potential mechanism to attenuate T cell inflammation. Alternatively, in BRCA1(mut) cancers retaining inflammation, STING upregulates VEGF-A, mediating immune resistance and tumor progression. Tumor-intrinsic STING elimination reduces neoangiogenesis, increases CD8(+) T cell infiltration, and reverts therapeutic resistance to dual immune checkpoint blockade (ICB). VEGF-A blockade phenocopies genetic STING loss and synergizes with ICB and/or poly(ADP-ribose) polymerase (PARP) inhibitors to control the outgrowth of Trp53(-/-) Brca1(-/-) but not Brca1(+/+) ovarian tumors in vivo, offering rational combinatorial therapies for HRD cancers.

Automated summary

This study investigates mechanisms of inflammation and immunoreactivity in ovarian tumors with homologous recombination deficiency (HRD). BRCA1 loss leads to transcriptional reprogramming and inflammation involving type I interferon (IFN) and STING. Genetic deletion or methylation of DNA-sensing/IFN genes or CCL5 chemokine can attenuate T cell inflammation. Tumor-intrinsic STING elimination reduces neoangiogenesis and reverses therapeutic resistance to immune checkpoint blockade. VEFG-A blockade synergizes with STING loss and immune checkpoint blockade to control tumor growth in HRD cancers.