Immunogenicity of BRCA1-deficient Ovarian Cancers is Driven through DNA Sensing and is Augmented by PARP Inhibition (Hi-C)

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. Overall design: The human ovarian cancer cell line UWB1.289,which harbors a deleterious mutation in BRCA1 exon11 and LOH, was profiled its chromatin structure by HiC. Same experimental procedure was followed for UWB1.289 BRCA1 wt reconstituted isogenic pair.