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Updated: Oct 7, 2025
Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
Published on: August 12, 2015
Disrupted BRCA1-PALB2 interaction induces tumor immunosuppression and T-lymphocyte infiltration in HCC through
Hui Ma1,2,3, Zhihua Kang2,3, Tzeh Keong Foo2,3
1Liver Cancer Institute , Zhongshan Hospital , Fudan University , Shanghai , China.
Background And Aims:
BRCA1 (BRCA1 DNA repair associated) and PALB2 (partner and localizer of BRCA2) interact with each other to promote homologous recombination and DNA double-strand breaks repair. The disruption of this interaction has been reported to play a role in tumorigenesis. However, its precise function in HCC remains poorly understood.
Approach And Results:
We demonstrated that mice with disrupted BRCA1-PALB2 interaction were more susceptible to HCC than wild-type mice. HCC tumors arising from these mice showed plenty of T-lymphocyte infiltration and a better response to programmed cell death 1 (PD-1) antibody treatment. Mechanistically, disruption of the BRCA1-PALB2 interaction causes persistent high level of DNA damage in HCC cells, leading to activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway in both malignant hepatocytes and M1 macrophages in the tumor microenvironment. The activated cGAS-STING pathway induces programmed cell death 1 ligand 1 expression via the STING-interferon regulatory factor 3 (IRF3)-signal transducer and activator of transcription 1 pathway, causing immunosuppression to facilitate tumorigenesis and tumor progression. Meanwhile, M1 macrophages with an activated cGAS-STING pathway could recruit T lymphocytes through the STING-IRF3 pathway, leading to T-lymphocyte infiltration in tumors. After normalizing immune responses by PD-1 antibody treatment, the infiltrating T lymphocytes attack tumor cells rapidly and effectively.
Conclusions:
This study reveals that persistent DNA damage caused by a defective BRCA pathway induces tumor immunosuppression and T-lymphocyte infiltration in HCC through the cGAS-STING pathway, providing insight into tumor immune microenvironment remodeling that may help improve HCC response to PD-1 antibody treatment.
Insights
Disrupting the BRCA1-PALB2 interaction in mice increases susceptibility to hepatocellular carcinoma (HCC). This defect activates the cGAS-STING pathway, causing immunosuppression and T-lymphocyte infiltration, which paradoxically improves response to PD-1 antibody treatment.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- BRCA1 and PALB2 proteins are crucial for DNA repair via homologous recombination.
- Disruption of the BRCA1-PALB2 interaction is implicated in tumorigenesis, but its role in hepatocellular carcinoma (HCC) is unclear.
- Understanding this interaction's role in HCC is vital for developing targeted therapies.
Purpose of the Study:
- To investigate the role of BRCA1-PALB2 interaction disruption in HCC development and immune microenvironment.
- To elucidate the underlying molecular mechanisms connecting DNA damage, immune response, and HCC progression.
- To assess the therapeutic potential of PD-1 antibody treatment in the context of BRCA1-PALB2 pathway defects.
Main Methods:
- Utilized a mouse model with disrupted BRCA1-PALB2 interaction to study HCC susceptibility.
- Analyzed tumor immune infiltration, including T-lymphocytes and M1 macrophages.
- Investigated the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway.
- Examined the expression of programmed cell death 1 ligand 1 (PD-L1) and its regulation via the STING-interferon regulatory factor 3 (IRF3) pathway.
- Assessed the efficacy of programmed cell death 1 (PD-1) antibody treatment.
Main Results:
- Mice with disrupted BRCA1-PALB2 interaction exhibited increased susceptibility to HCC.
- HCC tumors showed significant T-lymphocyte infiltration and responded better to PD-1 antibody treatment.
- Disruption led to persistent DNA damage, activating the cGAS-STING pathway in malignant hepatocytes and M1 macrophages.
- Activated cGAS-STING pathway upregulated PD-L1, causing immunosuppression and facilitating tumor progression.
- Activated M1 macrophages recruited T lymphocytes, contributing to tumor infiltration.
Conclusions:
- Defective BRCA pathway-induced DNA damage triggers tumor immunosuppression and T-lymphocyte infiltration in HCC via the cGAS-STING pathway.
- This study provides insights into tumor immune microenvironment remodeling in HCC.
- Findings may enhance the effectiveness of PD-1 antibody treatment for HCC patients with BRCA pathway defects.
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