期刊
AMERICAN JOURNAL OF CANCER RESEARCH
卷 12, 期 5, 页码 2363-+出版社
E-CENTURY PUBLISHING CORP
关键词
Immune checkpoint; DNA damage response; homologous recombination; non-homologous end joining; synthetic lethality; innate immunity
类别
资金
- National Natural Science Foundation of China [82172687, 81972186, 81572268]
- Natural Science Foundation of Tianjin [20JCYBJC25200]
- Health Commission of Tianjin [TJWJ2021MS002]
- Tianjin Key Medical Discipline (Specialty) Construction Project
PD-L1 plays a crucial role in DNA damage repair in cancer cells and can enhance the efficacy of existing immunotherapy by modulating pathways related to innate immunity.
Immunotherapies that block PD-L1/PD-1 immune checkpoint proteins represent a landmark breakthrough in cancer treatment. Although the role of PD-L1 in suppressing T cell activity has been extensively studied, its cancer cell-intrinsic functions are not well understood. Herein, we demonstrated that PD-L1 is important for the repair of DNA damage in cancer cells. Mechanically, depletion of PD-L1 led to the downregulation of the critical molecules involved in the homologous recombination (HR) repair pathway, such as ATM and BRCA1, but did not obviously affect the non-homologous end joining (NHEJ) pathway. Notably, PD-L1 silence sensitized cancer cells to chemotherapy agents and the inhibitor of DNA-PK, which is an important kinase for NHEJ. Furthermore, PD-L1 depletion potentiated DNA damage-induced cGAS-STING pathway and induction of IFN beta. The regulation of DNA repair and cGAS-STING pathway by PD-L1 represents its connection with innate immunity that can be exploited to enhance the efficacy of existing immunotherapy. Our findings thus expand the focus of PD-L1 from tumor antigen-specific CD8+ T cells to innate immunity, and support targeting tumor-intrinsic PD-L1 combined with DNA-PK inhibition for tumor eradication, through promoting synthetic lethality and innate immune response.
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