53BP1 loss elicits cGAS-STING-dependent antitumor immunity in ovarian and pancreatic cancer

Yajie Sun, Jeffrey Patterson-Fortin, Sen Han, Zhe Li, Zuzanna Nowicka, Yuna Hirohashi, Susan Kilgas, Jae Kyo Yi, Alexander Spektor, Wojciech Fendler, Panagiotis A. Konstantinopoulos and Dipanjan Chowdhury ()
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Yajie Sun: Harvard Medical School
Jeffrey Patterson-Fortin: Harvard Medical School
Sen Han: Harvard Medical School
Zhe Li: Harvard Medical School
Zuzanna Nowicka: Medical University of Lodz
Yuna Hirohashi: Harvard Medical School
Susan Kilgas: Harvard Medical School
Jae Kyo Yi: Harvard Medical School
Alexander Spektor: Harvard Medical School
Wojciech Fendler: Medical University of Lodz
Panagiotis A. Konstantinopoulos: Harvard Medical School
Dipanjan Chowdhury: Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract 53BP1 nucleates the anti-end resection machinery at DNA double-strand breaks, thereby countering BRCA1 activity. Loss of 53BP1 leads to DNA end processing and homologous recombination 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 double-stranded DNA, leading to activation of the cGAS-STING pathway and pro-inflammatory signaling. This enhances CD8+ T cell infiltration, activates macrophages and natural killer 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 and pancreatic ductal adenocarcinoma, which are refractory to ICBs, reveals that lower 53BP1 levels correlate 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.

Date: 2024
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DOI: 10.1038/s41467-024-50999-2

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