Deubiquitination and Stabilization of PD-L1 by CSN5

• Published in: Cancer cell Vol. 30; no. 6; pp. 925 - 939
• Main Authors: Lim, Seung-Oe, Li, Chia-Wei, Xia, Weiya, Cha, Jong-Ho, Chan, Li-Chuan, Wu, Yun, Chang, Shih-Shin, Lin, Wan-Chi, Hsu, Jung-Mao, Hsu, Yi-Hsin, Kim, Taewan, Chang, Wei-Chao, Hsu, Jennifer L., Yamaguchi, Hirohito, Ding, Qingqing, Wang, Yan, Yang, Yi, Chen, Chung-Hsuan, Sahin, Aysegul A., Yu, Dihua, Hortobagyi, Gabriel N., Hung, Mien-Chie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.12.2016
• Subjects: Animals; anti-CTLA4; B7-H1 Antigen - chemistry; B7-H1 Antigen - metabolism; Cell Line, Tumor; COP9 Signalosome Complex; CSN5; curcumin; Curcumin - pharmacology; deubiquitination; Female; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Mice; Neoplasm Transplantation; Neoplasms - metabolism; NF-kappa B - metabolism; PD-L1; Peptide Hydrolases - metabolism; Protein Stability; TNF-α; Tumor Necrosis Factor-alpha - metabolism; Ubiquitination; anti-CTLA4; CSN5; PD-L1; deubiquitination; TNF-α; curcumin
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2016.10.010

Pro-inflammatory cytokines produced in the tumor microenvironment lead to eradication of anti-tumor immunity and enhanced tumor cell survival. In the current study, we identified tumor necrosis factor alpha (TNF-α) as a major factor triggering cancer cell immunosuppression against T cell surveillance via stabilization of programmed cell death-ligand 1 (PD-L1). We demonstrated that COP9 signalosome 5 (CSN5), induced by NF-κB p65, is required for TNF-α-mediated PD-L1 stabilization in cancer cells. CSN5 inhibits the ubiquitination and degradation of PD-L1. Inhibition of CSN5 by curcumin diminished cancer cell PD-L1 expression and sensitized cancer cells to anti-CTLA4 therapy. [Display omitted] •TNF-α stabilizes cancer cell PD-L1 in response to chronic inflammation•Activation of NF-κB by TNF-α induces CSN5 expression leading to PD-L1 stabilization•CSN5 enzyme activity controls T cell suppression via PD-L1 deubiquitination•Destabilization of PD-L1 by CSN5 inhibitor curcumin benefits anti-CTLA4 therapy Lim et al. show that inflammation increases PD-L1 expression in tumors through TNF-α-mediated activation of NF-κB, leading to transactivation of CSN5. CSN5 reduces PD-L1 ubiquitination and stabilizes it. Inhibition of CSN5 cooperates with anti-CTLA4 to enhance anti-tumor T cell function and reduce tumor growth.