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

ABSTRACT: 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.

SUBMITTER: Bruand M

PROVIDER: S-EPMC8371260 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe present study was designed to test the hypothesis that inactivation of virtually any component within the pathway containing the BRCA1 and BRCA2 proteins would increase the risks for lymphomas and leukemias. In people who do not have BRCA1 or BRCA2 gene mutations, the encoded proteins prevent breast/ovarian cancer. However BRCA1 and BRCA2 proteins have multiple functions including participating in a pathway that mediates repair of DNA double strand breaks by error-free methods. Inactivation of BRCA1, BRCA2 or any other critical protein within this "BRCA pathway" due to a gene mutation should inactivate this error-free repair process. DNA fragments produced by double strand breaks are then left to non-specific processes that rejoin them without regard for preserving normal gene regulation or function, so rearrangements of DNA segments are more likely. These kinds of rearrangements are typically associated with some lymphomas and leukemias.MethodsLiterature searches produced about 2500 epidemiology and basic science articles related to the BRCA pathway. These articles were reviewed and copied to a database to facilitate access. Meta-analyses of statistical information compared risks for hematologic cancers vs. mutations for the components in a model pathway containing BRCA1/2 gene products.ResultsDeleterious mutations of genes encoding proteins virtually anywhere within the BRCA pathway increased risks up to nearly 2000 fold for certain leukemias and lymphomas. Cancers with large increases in risk included mantle cell lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, and prolymphocytic leukemia. Mantle cell lymphoma is defined by a characteristic rearrangement of DNA fragments interchanged between chromosomes 11 and 14. DNA translocations or rearrangements also occur in significant percentages of the other cancers.ConclusionAn important function of the BRCA pathway is to prevent a subgroup of human leukemias and lymphomas that may involve non-random, characteristic gene rearrangements. Here, the genetic defect in BRCA pathway deficiencies is a chromosomal misrepair syndrome that may facilitate this subgroup of somatic cancers. Inactivation of a single gene within the pathway can increase risks for multiple cancers and inactivation of a different gene in the same pathway may have similar effects. The results presented here may have clinical implications for surveillance and therapy.

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

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