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. 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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-50737A

DUB-IN-2

99.27%, Deubiquitinase Inhibitor

Deubiquitinase

Cancer

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