Deubiquitination and Stabilization of PD-L1 by CSN5

Publication date: Available online 17 November 2016
Source:Cancer Cell
Author(s): Seung-Oe Lim, Chia-Wei Li, Weiya Xia, Jong-Ho Cha, Li-Chuan Chan, Yun Wu, Shih-Shin Chang, Wan-Chi Lin, Jung-Mao Hsu, Yi-Hsin Hsu, Taewan Kim, Wei-Chao Chang, Jennifer L. Hsu, Hirohito Yamaguchi, Qingqing Ding, Yan Wang, Yi Yang, Chung-Hsuan Chen, Aysegul A. Sahin, Dihua Yu, Gabriel N. Hortobagyi, Mien-Chie Hung
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.

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Teaser

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.


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