Research uncovers mechanisms relating both to immunoreactivity, driven by DNA sensing and type-I IFN, and VEGFA-driven immune resistance, in BRCA1-mutated ovarian cancers.
This study, led by Denarda Dangaj and George Coukos, Director of the Ludwig Lausanne branch, investigates mechanisms leading to inflammation and immunoreactivity in ovarian tumors with homologous recombination deficiency (HRD).
BRCA1 loss was found to lead to transcriptional reprogramming in tumor cells and cell-intrinsic inflammation involving type I IFN and STING. BRCA1-mutated (BRCA1mut) ovarian cancers are thus T-cell inflamed at baseline. Genetic deletion or methylation of DNA-sensing/IFN genes or CCL5 chemokine were identified as potential mechanisms to attenuate T cell inflammation.
Researchers further found that in BRCA1mut 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 PARP inhibitors to control the outgrowth of Trp53-/-Brca1-/- but not Brca1+/+ ovarian tumors in vivo, offering rational combinatorial therapies for HRD cancers.
The paper is published in Cell Reports. Marine Bruand (former PhD in the TME and Biomarker discovery group of Dr Denarda Dangaj in the laboratoriy of Pr George Coukos, now part of the Oricchio Lab at EPFL) is first author.