Deubiquitination and Stabilization of PD-L1 by CSN5
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en diminuant l'expression de PD-L1 par les cellules cancéreuses, une stratégie basée sur l'inhibition de CSN5 rend ces cellules sensibles à une immunothérapie anti CTLA4
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-?B 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.