20220331 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 & Jinfang Zhang (2022). USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy. Nature Communications. （张金方）
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.
全文链接：
https://www.nature.com/articles/s41467-022-29401-6
