Targeting ubiquitin-specific protease 8 sensitizes anti-programmed death-ligand 1 immunotherapy of pancreatic cancer.

Hanshen Yang, Xiaozhen Zhang, Mengyi Lao, Kang Sun, Lihong He, Jian Xu, Yi Duan, Yan Chen, Honggang Ying, Muchun Li, Chengxiang Guo, Qingsong Lu, Sicheng Wang, Wei Su, Tingbo Liang, Xueli Bai

Cell death and differentiation 2023 Feb

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Programmed death-1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1) help tumor cells evade immune surveillance, and are regarded as important targets of anti-tumor immunotherapy. Post-translational modification of PD-L1 has potential value in immunosuppression. Here, we identified that ubiquitin-specific protease 8 (USP8) deubiquitinates PD-L1. Pancreatic cancer tissues exhibited significantly increased USP8 levels compared with those in normal tissues. Clinically, the expression of USP8 showed a significant association with the tumor-node-metastasis stage in multiple patient-derived cohorts of pancreatic cancer. Meanwhile, USP8 deficiency could reduce tumor invasion and migration and tumor size in an immunity-dependent manner, and improve anti-tumor immunogenicity. USP8 inhibitor pretreatment led to reduced tumorigenesis and immunocompetent mice with Usp8 knockdown tumors exhibited extended survival. Moreover, USP8 interacted positively with PD-L1 and upregulated its expression by inhibiting the ubiquitination-regulated proteasome degradation pathway in pancreatic cancer. Combination therapy with a USP8 inhibitor and anti-PD-L1 effectively suppressed pancreatic tumor growth by activation of cytotoxic T-cells and the anti-tumor immunity was mainly dependent on the PD-L1 pathway and CD8 + T cells. Our findings highlight the importance of targeting USP8, which can sensitize PD-L1-targeted pancreatic cancer to immunotherapy and might represent a novel therapeutic strategy to treat patients with pancreatic tumors in the future. © 2022. The Author(s).

Citation

Hanshen Yang, Xiaozhen Zhang, Mengyi Lao, Kang Sun, Lihong He, Jian Xu, Yi Duan, Yan Chen, Honggang Ying, Muchun Li, Chengxiang Guo, Qingsong Lu, Sicheng Wang, Wei Su, Tingbo Liang, Xueli Bai. Targeting ubiquitin-specific protease 8 sensitizes anti-programmed death-ligand 1 immunotherapy of pancreatic cancer. Cell death and differentiation. 2023 Feb;30(2):560-575