53BP1 loss elicits cGAS-STING-dependent antitumor immunity in ovarian and pancreatic cancer
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. Overall design: To investigate the clinical role of 53BP1 and its effect on the immune response, we established mouse Trp53bp1 knockout cell lines (ID8, KPC). We implanted these cell lines into syngeneic mice resulting in tumor formation. We then performed gene expression profiling analysis using data obtained from RNA-seq of 16 different tumors. Comparative gene expression profiling analysis of RNA-seq data for KPC tumors and its 53BP1 KO counterparts, or ID8 tumors and its 53BP1 KO counterparts.