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PARP inhibition elicits STING-dependent antitumor immune responses in Brca1-deficient ovarian cancer

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE120500 | GEO | 2019/02/13

REPOSITORIES: GEO

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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.

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PARP inhibition elicits STING-dependent antitumor immune responses in Brca1-deficient ovarian cancer

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