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

• DOI: 10.1016/j.celrep.2021.109412
• Publication Date: 2021-07-21T17:20:39Z
• Authors: Marine Bruand; David Barras; Marco Mina; Eleonora Ghisoni; Matteo Morotti; Evripidis Lanitis; Noémie Fahr; Mathieu Desbuisson; Alizée Grimm; Hualing Zhang; Chloe Chong; Julien Dagher; Sora Chee; Theodora Tsianou; Julien Dorier; Brian J. Stevenson; Christian Iseli; Catherine Ronet; Sara Bobisse; Raphael Genolet; Josephine Walton; Michal Bassani-St...; Lana E. Kandalaft; Bing Ren; Iain McNeish; Elizabeth Swisher; Alexandre Harari; Mauro Delorenzi; Giovanni Ciriello; Melita Irving; Sylvie Rusakiewicz; Periklis G. Foukas; Fabio Martinon; Denarda Dangaj La...; George Coukos
• Keywords: Immune checkpoint

In this study, we investigate mechanisms leading to inflammation and immunoreactivity in ovarian tumors with homologous recombination deficiency (HRD). BRCA1 loss is found lead transcriptional reprogramming tumor cells cell-intrinsic involving type I interferon (IFN) stimulator of IFN genes (STING). BRCA1-mutated (BRCA1mut) are thus T cell inflamed at baseline. Genetic deletion or methylation DNA-sensing/IFN CCL5 chemokine identified as a potential mechanism attenuate inflammation. Alternatively, BRCA1mut cancers retaining inflammation, STING upregulates VEGF-A, mediating immune resistance progression. Tumor-intrinsic elimination reduces neoangiogenesis, increases CD8+ infiltration, reverts therapeutic dual checkpoint blockade (ICB). VEGF-A phenocopies genetic synergizes ICB and/or poly(ADP-ribose) polymerase (PARP) inhibitors control the outgrowth Trp53−/−Brca1−/− but not Brca1+/+ vivo, offering rational combinatorial therapies for HRD cancers.