Targeting ubiquitin-specific protease 8 sensitizes anti-programmed death-ligand 1 immunotherapy of pancreatic cancer PMID: 36539510

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
8. Zhejiang Provincial Key Laboratory of Pancreatic Disease, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. [email protected].
9. Innovation Center for the Study of Pancreatic Diseases, Hangzhou, Zhejiang, China. [email protected].
10. Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Disease, Hangzhou, Zhejiang, China. [email protected].
11. Zhejiang University Cancer Center, Hangzhou, Zhejiang, China. [email protected].
12. Research Center for Healthcare Data Science, Zhejiang Lab, Hangzhou, Zhejiang, China. [email protected].
13. Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. [email protected].
14. Zhejiang Provincial Key Laboratory of Pancreatic Disease, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. [email protected].
15. Innovation Center for the Study of Pancreatic Diseases, Hangzhou, Zhejiang, China. [email protected].
16. Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Disease, Hangzhou, Zhejiang, China. [email protected].
17. Zhejiang University Cancer Center, Hangzhou, Zhejiang, China. [email protected].
18. Research Center for Healthcare Data Science, Zhejiang Lab, Hangzhou, Zhejiang, China. [email protected].
# Contributed equally.

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.