USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy

Wenjun Xiong, Xueliang Gao, Tiantian Zhang, Baishan Jiang, Ming-Ming Hu, Xia Bu, Yang Gao, Lin-Zhou Zhang, Bo-Lin Xiao, Chuan He, Yishuang Sun, Haiou Li, Jie Shi, Xiangling Xiao, Bolin Xiang, Conghua Xie, Gang Chen, Haojian Zhang, Wenyi Wei, Gordon J. Freeman, Hong-Bing Shu, Haizhen Wang () and Jinfang Zhang ()
Additional contact information
Wenjun Xiong: Zhongnan Hospital of Wuhan University
Xueliang Gao: Medical University of South Carolina
Tiantian Zhang: Wuhan University
Baishan Jiang: Wuhan University
Ming-Ming Hu: Wuhan University
Xia Bu: Harvard Medical School
Yang Gao: The First Affiliated Hospital of Xi’an Jiaotong University
Lin-Zhou Zhang: Wuhan University
Bo-Lin Xiao: Wuhan University
Chuan He: Zhongnan Hospital of Wuhan University
Yishuang Sun: Zhongnan Hospital of Wuhan University
Haiou Li: Wuhan University
Jie Shi: Zhongnan Hospital of Wuhan University
Xiangling Xiao: Zhongnan Hospital of Wuhan University
Bolin Xiang: Zhongnan Hospital of Wuhan University
Conghua Xie: Zhongnan Hospital of Wuhan University
Gang Chen: Wuhan University
Haojian Zhang: Wuhan University
Wenyi Wei: Harvard Medical School
Gordon J. Freeman: Harvard Medical School
Hong-Bing Shu: Wuhan University
Haizhen Wang: Medical University of South Carolina
Jinfang Zhang: Zhongnan Hospital of Wuhan University

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Anti-PD-1/PD-L1 immunotherapy has achieved impressive therapeutic outcomes in patients with multiple cancer types. However, the underlined molecular mechanism(s) for moderate response rate (15–25%) or resistance to PD-1/PD-L1 blockade remains not completely understood. Here, we report that inhibiting the deubiquitinase, USP8, significantly enhances the efficacy of anti-PD-1/PD-L1 immunotherapy through reshaping an inflamed tumor microenvironment (TME). Mechanistically, USP8 inhibition increases PD-L1 protein abundance through elevating the TRAF6-mediated K63-linked ubiquitination of PD-L1 to antagonize K48-linked ubiquitination and degradation of PD-L1. In addition, USP8 inhibition also triggers innate immune response and MHC-I expression largely through activating the NF-κB signaling. Based on these mechanisms, USP8 inhibitor combination with PD-1/PD-L1 blockade significantly activates the infiltrated CD8+ T cells to suppress tumor growth and improves the survival benefit in several murine tumor models. Thus, our study reveals a potential combined therapeutic strategy to utilize a USP8 inhibitor and PD-1/PD-L1 blockade for enhancing anti-tumor efficacy.

Date: 2022
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DOI: 10.1038/s41467-022-29401-6

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