USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy
Wenjun Xiong, Xueliang Gao, Tiantian Zhang, Baishan Jiang, Mingming 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, Jinfang Zhang
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.