Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity
dc.contributor.author
dc.date.accessioned
2020-01-13T12:56:23Z
dc.date.available
2020-01-13T12:56:23Z
dc.date.issued
2020-01-04
dc.identifier.issn
1945-4589
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dc.description.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
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application/pdf
dc.language.iso
eng
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Reproducció digital del document publicat a: https://doi.org/10.18632/aging.102646
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Aging (US), 2019, vol. undef, nún.undef, p.undef
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Articles publicats (D-CM)
dc.rights
Reconeixement 3.0 Espanya
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dc.source
Verdura, Sara Cuyàs, Elisabet Cortada, Eric Brunet i Vidal, Joan López Bonet, Eugeni Martin Castillo, Begoña Bosch Barrera, Joaquim Encinar, José Antonio Menéndez Menéndez, Javier Abel 2020 Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity. Aging-Us
dc.subject
dc.title
Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity
dc.type
info:eu-repo/semantics/article
dc.rights.accessRights
info:eu-repo/semantics/openAccess
dc.type.version
info:eu-repo/semantics/publishedVersion
dc.identifier.doi
dc.identifier.idgrec
030577
dc.type.peerreviewed
peer-reviewed