Deubiquitination and Stabilization of PD-L1 by CSN5

Highlights

• 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

Summary

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.