Approximately 10% of ovarian cancers are characterized by inherited mutations in the BRCA1 and BRCA2 genes. Researchers led by Ludwig Lausanne’s George Coukos and Denarda Dangaj Laniti explored the role of a double stranded DNA-sensing protein named STING, found in the cytoplasm of cells, in both driving immunoreactivity and promoting immune resistance in ovarian tumors with mutated BRCA genes. They reported in a July paper in Cell Reports that ovarian cancer cells with mutated BRCA genes induce inflammatory signals by activating STING and type 1 interferons (IFN), drawing T cells into such tumors. On the other hand, STING activation caused by the accumulation of double stranded DNA in the cytoplasm also promotes expression of VEGF-A, a critical regulator of blood vessel growth that drives tumor progression and immune evasion. In fact, the genetic loss of STING reduced VEGF-A expression and angiogenesis and increased T cell infiltration into tumors, an effect that could be mimicked by treatment with anti-VEGF-A antibodies. Combining an anti-VEGF-A antibody therapy with PARP inhibitors—which exacerbate double stranded DNA accumulation in BRCA-mutated cells—coupled with dual immune checkpoint blockade, suppressed BRCA-deficient ovarian tumors in mice. This suggests a new strategy for treating tumors with BRCA mutations or related deficiencies.
This article appeared in the February 2022 issue of Ludwig Link. Click here to download a PDF (1 MB).