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- Title
ARIH1 activates STING-mediated T-cell activation and sensitizes tumors to immune checkpoint blockade.
- Authors
Liu, Xiaolan; Cen, Xufeng; Wu, Ronghai; Chen, Ziyan; Xie, Yanqi; Wang, Fengqi; Shan, Bing; Zeng, Linghui; Zhou, Jichun; Xie, Bojian; Cai, Yangjun; Huang, Jinyan; Liang, Yingjiqiong; Wu, Youqian; Zhang, Chao; Wang, Dongrui; Xia, Hongguang
- Abstract
Despite advances in cancer treatment, immune checkpoint blockade (ICB) only achieves complete response in some patients, illustrating the need to identify resistance mechanisms. Using an ICB-insensitive tumor model, here we discover cisplatin enhances the anti-tumor effect of PD-L1 blockade and upregulates the expression of Ariadne RBR E3 ubiquitin-protein ligase 1 (ARIH1) in tumors. Arih1 overexpression promotes cytotoxic T cell infiltration, inhibits tumor growth, and potentiates PD-L1 blockade. ARIH1 mediates ubiquitination and degradation of DNA-PKcs to trigger activation of the STING pathway, which is blocked by the phospho-mimetic mutant T68E/S213D of cGAS protein. Using a high-throughput drug screen, we further identify that ACY738, less cytotoxic than cisplatin, effectively upregulates ARIH1 and activates STING signaling, sensitizing tumors to PD-L1 blockade. Our findings delineate a mechanism that tumors mediate ICB resistance through the loss of ARIH1 and ARIH1-DNA-PKcs-STING signaling and indicate that activating ARIH1 is an effective strategy to improve the efficacy of cancer immunotherapy. Loss of the E3 ubiquitin-protein ligase ARIH1 has been associated with cancer escape from anti-tumor immunity. Here the authors show that ARIH1 mediated ubiquitination and degradation of DNA-PKcs trigger activation of STING pathway in tumor cells, sensitizing tumors to immune checkpoint blockade.
- Subjects
PROGRAMMED cell death 1 receptors; UBIQUITINATION; IMMUNE checkpoint proteins; CYTOTOXIC T cells; T cells; TUMOR growth; TUMORS
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-39920-5