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

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 ge...

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Autores: Verdura, Sara, Cuyàs, Elisabet, Cortada, Eric, Brunet, Joan, López Bonet, Eugeni, Martin Castillo, Begoña, Bosch Barrera, Joaquim, Encinar, José Antonio, Menendez, Javier A.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/173234
Acceso en línea:https://hdl.handle.net/2445/173234
Access Level:acceso abierto
Palabra clave:Immunoteràpia
Cèl·lules T
Fenols
Immunotherapy
T cells
Phenols
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spelling Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunityVerdura, SaraCuyàs, ElisabetCortada, EricBrunet, JoanLópez Bonet, EugeniMartin Castillo, BegoñaBosch Barrera, JoaquimEncinar, José AntonioMenendez, Javier A.ImmunoteràpiaCèl·lules TFenolsImmunotherapyT cellsPhenolsNew 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.Impact Journals Llc2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/173234Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.18632/aging.102646Aging-us, 2020, vol. 12, num. 1, p. 8-34https://doi.org/10.18632/aging.102646cc by (c) Verdura et al. 2020http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1732342026-05-27T06:46:51Z
dc.title.none.fl_str_mv Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity
title Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity
spellingShingle Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity
Verdura, Sara
Immunoteràpia
Cèl·lules T
Fenols
Immunotherapy
T cells
Phenols
title_short Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity
title_full Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity
title_fullStr Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity
title_full_unstemmed Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity
title_sort Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity
dc.creator.none.fl_str_mv Verdura, Sara
Cuyàs, Elisabet
Cortada, Eric
Brunet, Joan
López Bonet, Eugeni
Martin Castillo, Begoña
Bosch Barrera, Joaquim
Encinar, José Antonio
Menendez, Javier A.
author Verdura, Sara
author_facet Verdura, Sara
Cuyàs, Elisabet
Cortada, Eric
Brunet, Joan
López Bonet, Eugeni
Martin Castillo, Begoña
Bosch Barrera, Joaquim
Encinar, José Antonio
Menendez, Javier A.
author_role author
author2 Cuyàs, Elisabet
Cortada, Eric
Brunet, Joan
López Bonet, Eugeni
Martin Castillo, Begoña
Bosch Barrera, Joaquim
Encinar, José Antonio
Menendez, Javier A.
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Immunoteràpia
Cèl·lules T
Fenols
Immunotherapy
T cells
Phenols
topic Immunoteràpia
Cèl·lules T
Fenols
Immunotherapy
T cells
Phenols
description 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.
publishDate 2020
dc.date.none.fl_str_mv 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/173234
url https://hdl.handle.net/2445/173234
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.18632/aging.102646
Aging-us, 2020, vol. 12, num. 1, p. 8-34
https://doi.org/10.18632/aging.102646
dc.rights.none.fl_str_mv cc by (c) Verdura et al. 2020
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Verdura et al. 2020
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Impact Journals Llc
publisher.none.fl_str_mv Impact Journals Llc
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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