Disrupted BRCA1-PALB2 interaction induces tumor immunosuppression and T-lymphocyte infiltration in HCC through cGAS-STING pathway.

ABSTRACT

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.