Similar Datasets
Project description:We investigated BRCA1-deficient ovarian cancer to understand why homologous recombination deficiency (HRD) is associated with tumor T-cell inflammation. In humans and mice, BRCA1 deficiency led to increased cytoplasmic translocation of nuclear DNA, increased DNA sensing, induction of proinflammatory cytokines and T-cell recruiting chemokines, and increased tumor CD8+ T-cell infiltration. This cascade was mediated by STING and phosphorylation of TBK1, IRF3 and STAT1. BRCA1 loss activated a transcriptional reprogramming of tumor cells, leading to overexpression of the DNA sensing pathway and hyper-responsiveness to cytoplasmic DNA. Genetic alterations of the DNA sensing and interferon pathways modulated the impact of HRD on T-cell inflammation. PARP inhibitor olaparib exacerbated cytoplasmic DNA and the cell-autonomous inflammatory activation of BRCA1-deficient cancers, and rendered them susceptible to PD-1/CTLA-4 blockade. We conclude that HRD and DNA sensing drives the immunogenicity of ovarian carcinomas and predisposes them to immune vulnerability under immune checkpoint blockade.
2021-06-16 | GSE122154 | GEO
Project description:We investigated BRCA1-deficient ovarian cancer to understand why homologous recombination deficiency (HRD) is associated with tumor T-cell inflammation. In humans and mice, BRCA1 deficiency led to increased cytoplasmic translocation of nuclear DNA, increased DNA sensing, induction of proinflammatory cytokines and T-cell recruiting chemokines, and increased tumor CD8+ T-cell infiltration. This cascade was mediated by STING and phosphorylation of TBK1, IRF3 and STAT1. BRCA1 loss activated a transcriptional reprogramming of tumor cells, leading to overexpression of the DNA sensing pathway and hyper-responsiveness to cytoplasmic DNA. Genetic alterations of the DNA sensing and interferon pathways modulated the impact of HRD on T-cell inflammation. PARP inhibitor olaparib exacerbated cytoplasmic DNA and the cell-autonomous inflammatory activation of BRCA1-deficient cancers, and rendered them susceptible to PD-1/CTLA-4 blockade. We conclude that HRD and DNA sensing drives the immunogenicity of ovarian carcinomas and predisposes them to immune vulnerability under immune checkpoint blockade.
2021-06-16 | GSE122153 | GEO
Project description:Immunogenicity of BRCA1-deficient Ovarian Cancers is Driven through DNA Sensing and is Augmented by PARP Inhibition
| PRJNA503840 | ENA
Project description:Immunogenicity of BRCA1-deficient Ovarian Cancers is Driven through DNA Sensing and is Augmented by PARP Inhibition (ChIP-Seq)
| PRJNA503844 | ENA
Project description:Immunogenicity of BRCA1-deficient Ovarian Cancers is Driven through DNA Sensing and is Augmented by PARP Inhibition (Hi-C)
| PRJNA503846 | ENA
Project description:BRCA1 is an essential gene of the homologous recombination repair (HR) pathway. Ovarian cancers with BRCA1 mutations represent about 20% of HGSOC and are characterized by loss-of-function TP53 mutations, copy number alterations, chromosomal instability, high neoantigen loads and increased infiltration of intraepithelial CD8 tumor-infiltrating lymphocytes (TILs). We propose that DNA damage induced by BRCA1 loss could be a tumor-autonomous inflammatory mechanism. Our hypothesis was corroborated by studies in human and mouse isogenic ovarian cancer cell lines which revealed that BRCA1 deficiency leads to increased cytoplasmic gamma H2AX+ double stranded (ds) DNA species, overexpression of proteins of the nucleic acid sensor pathway (IFI16, STING, MX1), phosphorylation of TBK1, IRF3 and STAT1 and secretion of pro-inflammatory cytokines (IFN-b, IFN-a) and T cell recruiting chemokines (CCL5, CXCL9, CXCL10). PARP inhibition exacerbated type I IFN responses in BRCA1 deficient ovarian cancer cell lines and simultaneously increased surface expression of PDL1. Increased DNA damage, as measured by γH2AX tumor staining, was also detected in situ in human ovarian cancers with BRCA1 mutations. Importantly, we detected tumor expression of pSTAT1 confirming a type I IFN activation in tumors with DNA damage. Both DNA damage and pSTAT1 activation correlated with higher TIL infiltration and better overall survival. Our results translated in mouse models of ovarian cancer where Trp53-/-Brca1-/- but not Trp53-/-Brca1WT tumors presented with biomarkers of DNA damage, type I IFN pathway activation and responded to a therapeutic combination of PARP inhibitor Olaparib with dual checkpoint blockade antibodies. Our results provide a mechanistic link between loss of BRCA1 and induction of tumor-driven inflammatory and immunogenic responses in ovarian cancer that was mediated by tumor-cell autonomous type I IFN signaling. which translated to increased immune surveillance by CD8 T cells.
2021-06-16 | GSE120792 | GEO
Project description:PARP inhibitors have shown promising clinical activities for patients with BRCA mutations and are changing the landscape of ovarian cancer treatment. However, the therapeutic mechanisms of action for PARP inhibition in the interaction of tumors with the tumor microenvironment and the host immune system remain unclear. We find that PARP inhibition by olaparib triggers robust local and systemic antitumor immunity involving both adaptive and innate immune responses through a STING-dependent antitumor immune response in mice bearing Brca1-deficient ovarian tumors. This effect is further augmented when olaparib is combined with PD-1 blockade. Our findings thus provide a molecular mechanism underlying antitumor activity by PARP inhibition and lay a foundation to improve therapeutic outcome for cancer patients.
| S-EPMC6366450 | biostudies-literature
Project description:Immune checkpoint blockade has shown significant therapeutic efficacy in melanoma and other solid tumors, but results in ovarian cancer have been limited. With evidence that tumor immunogenicity modulates the response to checkpoint blockade, and data indicating that BRCA-deficient ovarian cancers express higher levels of immune response genes, we hypothesized that BRCA(-) ovarian tumors would be vulnerable to checkpoint blockade. To test this hypothesis, we used an immunocompetent BRCA1-deficient murine ovarian cancer model to compare treatment with CTLA-4 or PD-1/PD-L1 antibodies alone or combined with targeted cytotoxic therapy using a PARP inhibitor. Correlative studies were performed in vitro using human BRCA1(-) cells. We found that CTLA-4 antibody, but not PD-1/PD-L1 blockade, synergized therapeutically with the PARP inhibitor, resulting in immune-mediated tumor clearance and long-term survival in a majority of animals (P < 0.0001). The survival benefit of this combination was T-cell mediated and dependent on increases in local IFN? production in the peritoneal tumor environment. Evidence of protective immune memory was observed more than 60 days after completion of therapy. Similar increases in the cytotoxic effect of PARP inhibition in the presence of elevated levels of IFN? in human BRCA1(-) cancer cells support the translational potential of this treatment protocol. These results demonstrate that CTLA-4 blockade combined with PARP inhibition induces protective antitumor immunity and significant survival benefit in the BRCA1(-) tumor model, and support clinical testing of this regimen to improve outcomes for women with hereditary ovarian cancer.
| S-EPMC4984269 | biostudies-literature
Project description:Inhibition of poly(ADP-ribose) polymerase (PARP) is a promising therapeutic strategy for BRCA1 deficient cancers, however, the development of drug resistance limits clinical efficacy. Previously we found that the BRCA1-AKT1 pathway contributes to tumorigenesis and that the AKT1/mTOR is a novel therapeutic target for BRCA1-deficient cancers. Here, we report that phosphorylation of ribosomal protein S6, a mTOR downstream effector, is greatly increased in BRCA1 deficient cells resistant to PARP inhibition. Phosphorylation of S6 is associated with DNA damage and repair signaling during PARP inhibitor treatment. In BRCA1 deficient cells, expression of S6 lacking all five phosphorylatable sites renders the cells sensitive to PARP inhibitor and increases DNA damage signals. In addition, the S6 mutations reduce tumor formation induced by Brca1-deficiency in mice. Inhibition of S6 phosphorylation by rapamycin restores PARP sensitivity to resistant cells. Combined treatment with rapamycin and PARP inhibitor effectively suppresses BRCA1-deficient tumor growth in mice. These results provide evidence for a novel mechanism by which BRCA1 deficient cancers acquire drug resistance and suggest a new therapeutic strategy to circumvent resistance.
| S-EPMC4102816 | biostudies-literature
Project description:To examine the immune responses that occur in Brca1-deficent tumors upon olaparib treatment, we performed gene expression analysis of a panel of 4604 cancer and immune-related genes in tumor tissues harvested from Brca1-deficient ovarian tumor-bearing mice after treatment with olaparib or vehicle. Transcriptome analysis showed that the expression of genes associated with immune response, T-cell activation and interferon-gamma(IFNgamma) response were markedly upregulated in tumors treated with olaparib as compared to vehicle. Our data reveal the antitumor immune response of PARP inhibition and demonstrate that it contributes to therapeutic efficacy of PARP inhibition in Brca1-deficient tumors.
2019-02-13 | GSE120500 | GEO