USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy

• Published in: Nature communications Vol. 13; no. 1; pp. 1700 - 17
• Main Authors: Xiong, Wenjun, Gao, Xueliang, Zhang, Tiantian, Jiang, Baishan, Hu, Ming-Ming, Bu, Xia, Gao, Yang, Zhang, Lin-Zhou, Xiao, Bo-Lin, He, Chuan, Sun, Yishuang, Li, Haiou, Shi, Jie, Xiao, Xiangling, Xiang, Bolin, Xie, Conghua, Chen, Gang, Zhang, Haojian, Wei, Wenyi, Freeman, Gordon J., Shu, Hong-Bing, Wang, Haizhen, Zhang, Jinfang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31.03.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 38/88; 45/90; 45/91; 631/337/458/582; 631/67/327; 64/60; Animal models; Animals; Anticancer properties; CD8 antigen; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Endopeptidases - genetics; Endosomal Sorting Complexes Required for Transport - genetics; Humanities and Social Sciences; Humans; Immune response; Immune system; Immunotherapy; Inflammation; Inhibitors; Innate immunity; L1 protein; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Mice; multidisciplinary; Neoplasms - drug therapy; Neoplasms - genetics; NF-κB protein; PD-1 protein; PD-L1 protein; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Proteins; Regulatory mechanisms (biology); Science; Science (multidisciplinary); Signaling; TRAF6 protein; Tumor Microenvironment; Tumors; Ubiquitin Thiolesterase - antagonists & inhibitors; Ubiquitin Thiolesterase - genetics; Ubiquitination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-29401-6

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. The regulatory mechanisms of PD-L1 posttranslational modifications are not completely understood. Here the authors show that USP8 negatively regulates PD-L1 protein abundance by removing the K63-linked ubiquitination of PD-L1; while USP8 inhibition increases MHC-I expression and triggers anti-tumour immune responses through activating NF-κB signalling.