PARP inhibition elicits STING-dependent antitumor immune responses in Brca1-deficient ovarian cancer
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ABSTRACT:
PROVIDER: PRJNA493223 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR7904500.fastq.gz | Fastqsanger.gz | |||
| SRR7904501.fastq.gz | Fastqsanger.gz | |||
| SRR7904502.fastq.gz | Fastqsanger.gz | |||
| SRR7904503.fastq.gz | Fastqsanger.gz | |||
| SRR7904504.fastq.gz | Fastqsanger.gz |
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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
Project description:PARP inhibitors (PARPi) have drastically changed the treatment landscape of advanced ovarian tumors with BRCA mutations. However, the impact of this class of inhibitors in patients with advanced BRCA-mutant breast cancer is relatively modest. Using a syngeneic genetically-engineered mouse model of breast tumor driven by Brca1 deficiency, we show that tumor-associated macrophages (TAMs) blunt PARPi efficacy both in vivo and in vitro. Mechanistically, BRCA1-deficient breast tumor cells induce pro-tumor polarization of TAMs, which in turn suppress PARPi-elicited DNA damage in tumor cells, leading to reduced production of dsDNA fragments and synthetic lethality, hence impairing STING-dependent anti-tumor immunity. STING agonists reprogram M2-like pro-tumor macrophages into an M1-like anti-tumor state in a macrophage STING-dependent manner. Systemic administration of a STING agonist breaches multiple layers of tumor cell-mediated suppression of immune cells, and synergizes with PARPi to suppress tumor growth. The therapeutic benefits of this combination require host STING and are mediated by a type I IFN response and CD8+ T cells, but do not rely on tumor cell-intrinsic STING. Our data illustrate the importance of targeting innate immune suppression to facilitate PARPi-mediated engagement of anti-tumor immunity in breast cancer.
2022-04-21 | GSE201017 | GEO
Project description:BRCA1 loss leads to tumor cell transcriptional reprogramming, resulting in a DNA damage-driven, mandatory cell-autonomous type I IFN inflammatory activation mediated by STING and TREX1/2. PARP inhibition augmented this immunoreactivity, creating contextual lethality to dual immune checkpoint blockade (ICB) in vivo. BRCA1-deficient tumor can escape T-cell inflammation through targeted deletion or methylation of the DNA sensing/IFN pathway genes, such as STING, IFNB1 or the chemokine CCL5. Alternatively, BRCA-mutated carcinomas retaining immunoreactivity upregulate their VEGF-A expression driven by STING, which mediates immune resistance and tumor progression. STING elimination attenuated tumor growth and abrogated therapeutic resistance to dual ICB. VEGF-A blockade synergized with immune checkpoint blockade and/or PARP inhibition to control outgrowth of Brca1-/- ovarian tumors, offering opportunities for rational combination therapy of cancers with homologous recombination repair deficiency (HRD).
2021-06-16 | GSE162935 | 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:53BP1 nucleates the anti-end resection machinery at DNA double-strand breaks (DSBs), thereby countering BRCA1 activity. Loss of 53BP1 leads to DNA end processing and homologous recombination (HR) in BRCA1-deficient cells. Consequently, BRCA1-mutant tumors, typically sensitive to PARP inhibitors (PARPi), become resistant in the absence of 53BP1. Here, we demonstrate that the 'leaky' DNA end resection in the absence of 53BP1 results in increased micronuclei and cytoplasmic dsDNA, leading to activation of the cGAS-STING pathway and pro-inflammatory signaling. This enhances CD8+ T cell infiltration, activates macrophages and natural killer (NK) cells, and impedes tumor growth. Loss of 53BP1 correlates with a response to immune checkpoint blockade (ICB) and improved overall survival. Immunohistochemical assessment of 53BP1 in two malignancies, high grade serous ovarian cancer (HGSOC)s and pancreatic ductal adenocarcinoma (PDAC)s, which are refractory to ICBs, revealed that lower 53BP1 levels correlated with an increased adaptive and innate immune response. Finally, BRCA1-deficient tumors that develop resistance to PARPi due to the loss of 53BP1 are susceptible to ICB. Therefore, we conclude that 53BP1 is critical for tumor immunogenicity and underpins the response to ICB. Our results support including 53BP1 expression as an exploratory biomarker in ICB trials for malignancies typically refractory to immunotherapy.
2024-07-09 | GSE237615 | GEO
Project description:Despite numerous therapeutic advances over the years, ovarian cancer, especially high grade serous ovarian carcinoma remains the deadliest gynecological malignancy. Although PARP inhibition has been shown to be an effective (maintenance) therapy for homologous recombination repair deficient or BRCA1 mutated ovarian cancer, there may be further potential for combination therapy with other drugs such as immune checkpoint inhibitors. BRCA1 mutation as well as PARP inhibitor (Olaparib) treatment influenced the activation of immune response pathways such as cGAS-STING signaling and Interferon-alpha response in ovarian cancer cell lines. Bioinformatics functional analyses uncovered further immune related cellular responses and signaling pathways such as JAK-STAT signaling.
2023-08-01 | GSE237361 | GEO
Project description:53BP1 loss elicits cGAS-STING-dependent antitumor immunity in ovarian and pancreatic cancer
| PRJNA996040 | ENA
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: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