PD-L1 deficiency sensitizes tumor cells to DNA-PK inhibition and enhances cGAS-STING activation
Zhen Xue1,2, Shuang Zheng1,2, Dongli Linghu1
1Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital Tianjin 300052, P. R. China.
Abstract:
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 IFNβ. 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.
Insights
Programmed death-ligand 1 (PD-L1) aids cancer cells in repairing DNA damage via homologous recombination. Targeting PD-L1 enhances chemotherapy and immunotherapy efficacy by affecting DNA repair and innate immunity.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Programmed death-ligand 1 (PD-L1) and its interaction with PD-1 are key targets in cancer immunotherapy, primarily known for modulating T cell responses.
- The intrinsic functions of PD-L1 within cancer cells, beyond immune suppression, remain largely unexplored.
Purpose of the Study:
- To investigate the role of PD-L1 in DNA damage repair mechanisms within cancer cells.
- To explore the impact of PD-L1 on cancer cell sensitivity to DNA-damaging agents and its connection to innate immunity.
Main Methods:
- Depletion of PD-L1 in cancer cells using gene silencing techniques.
- Assessment of DNA repair pathway activity, specifically homologous recombination (HR) and non-homologous end joining (NHEJ).
- Evaluation of cancer cell sensitivity to chemotherapy and DNA-PK inhibitors, and analysis of the cGAS-STING pathway activation.
Main Results:
- PD-L1 depletion downregulated key homologous recombination (HR) repair molecules like ATM and BRCA1, without significantly affecting non-homologous end joining (NHEJ).
- Silencing PD-L1 sensitized cancer cells to chemotherapy and DNA-PK inhibitors, indicating a role in DNA repair fidelity.
- PD-L1 inhibition potentiated DNA damage-induced activation of the cGAS-STING pathway and interferon-beta (IFNβ) production, linking PD-L1 to innate immune signaling.
Conclusions:
- PD-L1 plays a crucial role in intrinsic DNA damage repair in cancer cells, primarily through the HR pathway.
- Targeting tumor-intrinsic PD-L1, particularly in combination with DNA-PK inhibition, offers a strategy to induce synthetic lethality and enhance innate immune responses for tumor eradication.
- These findings broaden the understanding of PD-L1's function beyond T cell modulation to include innate immunity, suggesting novel therapeutic avenues.
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