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Title: Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity
Author: Verdura, Sara
Cuyàs, Elisabet
Cortada, Eric
Brunet, Joan
Lopez Bonet, Eugeni
Martin Castillo, Begoña
Bosch Barrera, Joaquim
Encinar, José Antonio
Menendez, Javier A.
Keywords: Immunoteràpia
Cèl·lules T
T cells
Issue Date: 15-Jan-2020
Publisher: Impact Journals Llc
Abstract: New 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.
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It is part of: Aging-us, 2020, vol. 12, num. 1, p. 8-34
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Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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