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

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

  • Cell Death Differ. 2022 Dec 20. doi: 10.1038/s41418-022-01102-z.
Hanshen Yang # 1 2 3 4 5 6,  Xiaozhen Zhang # 1 2 3 4 5 6,  Mengyi Lao 1 2 3 4 5 6,  Kang Sun 1 2 3 4 5 6,  Lihong He 1 2 3 4 5 6,  Jian Xu 1 2 3 4 5 6,  Yi Duan 1 2 3 4 5 6,  Yan Chen 1 2 3 4 5 6,  Honggang Ying 1 2 3 4 5 6,  Muchun Li 1 2 3 4 5 6,  Chengxiang Guo 1 2 3 4 5 6,  Qingsong Lu 1 2 3 4 5 6,  Sicheng Wang 1 2 3 4 5 6,  Wei Su 1 2 3 4 5 6,  Tingbo Liang 7 8 9 10 11 12,  Xueli Bai 13 14 15 16 17 18
Affiliations

Affiliations

  • 1 Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • 2 Zhejiang Provincial Key Laboratory of Pancreatic Disease, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • 3 Innovation Center for the Study of Pancreatic Diseases, Hangzhou, Zhejiang, China.
  • 4 Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Disease, Hangzhou, Zhejiang, China.
  • 5 Zhejiang University Cancer Center, Hangzhou, Zhejiang, China.
  • 6 Research Center for Healthcare Data Science, Zhejiang Lab, Hangzhou, Zhejiang, China.
  • 7 Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. liangtingbo@zju.edu.cn.
  • 8 Zhejiang Provincial Key Laboratory of Pancreatic Disease, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. liangtingbo@zju.edu.cn.
  • 9 Innovation Center for the Study of Pancreatic Diseases, Hangzhou, Zhejiang, China. liangtingbo@zju.edu.cn.
  • 10 Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Disease, Hangzhou, Zhejiang, China. liangtingbo@zju.edu.cn.
  • 11 Zhejiang University Cancer Center, Hangzhou, Zhejiang, China. liangtingbo@zju.edu.cn.
  • 12 Research Center for Healthcare Data Science, Zhejiang Lab, Hangzhou, Zhejiang, China. liangtingbo@zju.edu.cn.
  • 13 Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. shirleybai@zju.edu.cn.
  • 14 Zhejiang Provincial Key Laboratory of Pancreatic Disease, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. shirleybai@zju.edu.cn.
  • 15 Innovation Center for the Study of Pancreatic Diseases, Hangzhou, Zhejiang, China. shirleybai@zju.edu.cn.
  • 16 Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Disease, Hangzhou, Zhejiang, China. shirleybai@zju.edu.cn.
  • 17 Zhejiang University Cancer Center, Hangzhou, Zhejiang, China. shirleybai@zju.edu.cn.
  • 18 Research Center for Healthcare Data Science, Zhejiang Lab, Hangzhou, Zhejiang, China. shirleybai@zju.edu.cn.
  • # Contributed equally.
PMID: 36539510 DOI: 10.1038/s41418-022-01102-z
Abstract

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.

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