PD-L1 deficiency sensitizes tumor cells to DNA-PK inhibition and enhances cGAS-STING activation.

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.

• Authors: Zhen Xue, Shuang Zheng, Dongli Linghu, Boning Liu, Yi Yang, Mei-Kuang Chen, Hua Huang, Jiaming Song, Hongyue Li, Jing Wang, Mien-Chie Hung, Diansheng Zhong, Linlin Sun
• Journal: American journal of cancer research (Am J Cancer Res) Vol. 12 Issue 5 Pg. 2363-2375 ( 2022) ISSN: 2156-6976 [Print] United States
• PMID: 35693073 (Publication Type: Journal Article)
• Copyright: AJCR Copyright © 2022.