Chronic Inflammation Promotes CSN5-Mediated PD-L1 Stabilization

Cancer cells can evade immune surveillance in part through expression of the inhibitory programmed cell death-ligand 1 (PD-L1) on their cell surface. Although transcriptional mechanisms of PD-L1 regulation have been described, the mechanisms by which PD-L1 is post-translationally regulated have not been well elucidated. Lim, Li, and colleagues investigated antitumor immunity in a mouse model of inflammation, finding that inflammation enhanced tumor growth and increased the number of tumor-infiltrating lymphocytes and macrophages, but reduced the cytotoxic activity of T cells, indicating that inflammation prevents T-cell antitumor activity. In breast cancer cells, inflammatory cytokines released by macrophages induced upregulation of PD-L1 protein, but not mRNA, indicative of post-translational regulation. Mechanistically, inflammation induced macrophages to secrete TNFα that activated tumor cell NF-κB signaling, allowing the p65 subunit to bind to the promoter and enhance transcription of COP9 signalosome 5 (CSN5; also known as COPS5). CSN5 encodes a deubiquitinating enzyme that was found to deubiquitinate and stabilize PD-L1, resulting in enhanced PD-L1 expression in response to inflammatory TNFα signaling. Further, the CSN5 inhibitor curcumin blocked TNFα-induced PD-L1 stabilization in multiple cancer cell types. In breast cancer cell lines and in tissue from patients with breast cancer, CSN5 expression was correlated with expression of PD-L1, providing support for the in vitro findings. Moreover, elevated CSN5 expression was associated with shorter survival in patients with breast cancer. Anti-PD1 antibodies have been combined with anti-CTLA4 antibodies in clinical trials, providing a rationale for testing curcumin in combination with CTLA4 blockade. Curcumin enhanced the therapeutic efficacy of anti-CTLA4 in mice, resulting in reduced tumor burden, increased survival, and an increase in active tumor-infiltrating CD8⁺ T cells. In addition, curcumin plus anti-CTLA4 was effective in reducing tumor growth in noninflammatory conditions. Collectively, these findings indicate that CSN5 stabilizes PD-L1 to promote tumor immune evasion and that inhibition of CSN5 may be effective in combination with other immunotherapies.

Lim SO, Li CW, Xia W, Cha JH, Chan LC, Wu Y, et al. Deubiquitination and stabilization of PD-L1 by CSN5. Cancer Cell 2016;30:925–39.

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