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53BP1 loss elicits cGAS-STING-dependent antitumor immunity in ovarian and pancreatic cancer
Yajie Sun1,2, Jeffrey Patterson-Fortin1,3, Sen Han4
1Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
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.
Insights
Loss of 53BP1 in BRCA1-deficient tumors activates anti-tumor immunity, making them responsive to immune checkpoint blockade (ICB). This finding suggests 53BP1 as a biomarker for ICB therapy in difficult-to-treat cancers.
Area of Science:
- DNA repair mechanisms
- Tumor immunology
- Cancer therapy
Background:
- 53BP1 protein is crucial for DNA double-strand break repair and counteracts BRCA1 activity.
- Loss of 53BP1 confers resistance to PARP inhibitors (PARPi) in BRCA1-deficient cancers.
- BRCA1-deficient tumors are typically sensitive to PARPi, but 53BP1 loss reverses this sensitivity.
Purpose of the Study:
- To investigate the impact of 53BP1 loss on tumor immunogenicity and response to immune checkpoint blockade (ICB).
- To explore the role of DNA end resection and cGAS-STING pathway activation in the absence of 53BP1.
- To evaluate 53BP1 as a potential biomarker for ICB therapy in refractory malignancies.
Main Methods:
- Analysis of DNA end resection, micronuclei formation, and cytoplasmic DNA in cells lacking 53BP1.
- Assessment of cGAS-STING pathway activation and immune cell infiltration (CD8+ T cells, macrophages, NK cells).
- Immunohistochemical evaluation of 53BP1 levels in ovarian and pancreatic cancer patient samples and correlation with immune response and survival.
Main Results:
- Loss of 53BP1 leads to 'leaky' DNA end resection, increased micronuclei, and cytoplasmic DNA, activating the cGAS-STING pathway.
- This activation enhances anti-tumor immunity, including CD8+ T cell infiltration and activation of innate immune cells, impeding tumor growth.
- Lower 53BP1 levels correlate with increased immune response and improved survival in ovarian and pancreatic cancers, and restore ICB sensitivity in PARPi-resistant tumors.
Conclusions:
- 53BP1 is a critical regulator of tumor immunogenicity and dictates response to immune checkpoint blockade.
- Loss of 53BP1 renders BRCA1-deficient tumors susceptible to ICB, even after developing PARPi resistance.
- 53BP1 expression can serve as an exploratory biomarker for identifying patients who may benefit from ICB, particularly in refractory cancers.
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