Verdura, SaraCuyàs, ElisabetCortada, EricBrunet, JoanLópez Bonet, EugeniMartin Castillo, BegoñaBosch Barrera, JoaquimEncinar, José AntonioMenendez, Javier A.2021-01-202021-01-202020-01-15https://hdl.handle.net/2445/173234New strategies to block the immune evasion activity of programmed death ligand-1 (PD-L1) are urgently needed. When exploring the PD-L1-targeted effects of mechanistically diverse metabolism-targeting drugs, exposure to the dietary polyphenol resveratrol (RSV) revealed its differential capacity to generate a distinct PD-L1 electrophoretic migration pattern. Using biochemical assays, computer-aided docking/molecular dynamics simulations, and fluorescence microscopy, we found that RSV can operate as a direct inhibitor of glyco-PD-L1-processing enzymes (alpha-glucosidase/alpha-mannosidase) that modulate N-linked glycan decoration of PD-L1, thereby promoting the endoplasmic reticulum retention of a mannose-rich, abnormally glycosylated form of PD-L1. RSV was also predicted to interact with the inner surface of PD-L1 involved in the interaction with PD-1, almost perfectly occupying the target space of the small compound BMS-202 that binds to and induces dimerization of PD-L1. The ability of RSV to directly target PD-L1 interferes with its stability and trafficking, ultimately impeding its targeting to the cancer cell plasma membrane. Impedance-based real-time cell analysis (xCELLigence) showed that cytotoxic T-lymphocyte activity was notably exacerbated when cancer cells were previously exposed to RSV. This unforeseen immunomodulating mechanism of RSV might illuminate new approaches to restore T-cell function by targeting the PD-1/PD-L1 immunologic checkpoint with natural polyphenols.27 p.application/pdfengcc by (c) Verdura et al. 2020http://creativecommons.org/licenses/by/3.0/es/ImmunoteràpiaCèl·lules TFenolsImmunotherapyT cellsPhenolsinfo:eu-repo/semantics/article2020-12-21info:eu-repo/semantics/openAccess31901900