Please use this identifier to cite or link to this item: https://hdl.handle.net/11000/30654

Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity


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Title:
Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity
Authors:
Verdura, Sara  
Cuyàs, Elisabet  
Cortada Almar, Eric  
Brunet, Joan  
López-Bonet, Eugeni  
Martín-Castillo, Begoña  
Bosch-Barrera, Joaquim  
Encinar, José Antonio  
MENÉNDEZ MENÉNDEZ, JAVIER ABEL  
Editor:
Impact Journals
Department:
Departamentos de la UMH::Bioquímica y Biología Molecular
Issue Date:
2019-12-23
URI:
https://hdl.handle.net/11000/30654
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 (α-glucosidase/α-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.
Keywords/Subjects:
PD-L1
resveratrol
immunotherapy
T cells
glycosylation
Knowledge area:
CDU: Ciencias puras y naturales: Biología: Bioquímica. Biología molecular. Biofísica
Type of document:
application/pdf
Access rights:
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 Internacional
DOI:
https://doi.org/10.18632/aging.102646
Appears in Collections:
Artículos Bioquímica y Biología Molecular



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