Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity
Identifieur interne : 000D96 ( Ncbi/Merge ); précédent : 000D95; suivant : 000D97Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity
Auteurs : Sara Verdura [Espagne] ; Elisabet Cuyàs [Espagne] ; Eric Cortada [Espagne] ; Joan Brunet [Espagne] ; Eugeni Lopez-Bonet [Espagne] ; Bego A Martin-Castillo [Espagne] ; Joaquim Bosch-Barrera [Espagne] ; José Antonio Encinar [Espagne] ; Javier A. Menendez [Espagne]Source :
- Aging (Albany NY) [ 1945-4589 ] ; 2020.
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
Url:
DOI: 10.18632/aging.102646
PubMed: 31901900
PubMed Central: 6977679
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<front><div type="abstract" xml:lang="en"><p>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 <italic>N</italic>
-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.</p>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Aging (Albany NY)</journal-id>
<journal-id journal-id-type="iso-abbrev">Aging (Albany NY)</journal-id>
<journal-id journal-id-type="publisher-id">Aging</journal-id>
<journal-title-group><journal-title>Aging (Albany NY)</journal-title>
</journal-title-group>
<issn pub-type="epub">1945-4589</issn>
<publisher><publisher-name>Impact Journals</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31901900</article-id>
<article-id pub-id-type="pmc">6977679</article-id>
<article-id pub-id-type="doi">10.18632/aging.102646</article-id>
<article-id pub-id-type="publisher-id">102646</article-id>
<article-id pub-id-type="publisher-id">102646</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Priority Research Paper</subject>
</subj-group>
</article-categories>
<title-group><article-title>Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Verdura</surname>
<given-names>Sara</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="author-notes" rid="F1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cuyàs</surname>
<given-names>Elisabet</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="author-notes" rid="F1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cortada</surname>
<given-names>Eric</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
<xref ref-type="aff" rid="aff4"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Brunet</surname>
<given-names>Joan</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>5</sup>
</xref>
<xref ref-type="aff" rid="aff6"><sup>6</sup>
</xref>
<xref ref-type="aff" rid="aff7"><sup>7</sup>
</xref>
<xref ref-type="aff" rid="aff8"><sup>8</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lopez-Bonet</surname>
<given-names>Eugeni</given-names>
</name>
<xref ref-type="aff" rid="aff9"><sup>9</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Martin-Castillo</surname>
<given-names>Begoña</given-names>
</name>
<xref ref-type="aff" rid="aff10"><sup>10</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bosch-Barrera</surname>
<given-names>Joaquim</given-names>
</name>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="aff" rid="aff5"><sup>5</sup>
</xref>
<xref ref-type="aff" rid="aff6"><sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Encinar</surname>
<given-names>José Antonio</given-names>
</name>
<xref ref-type="aff" rid="aff11"><sup>11</sup>
</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Menendez</surname>
<given-names>Javier A.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<aff id="aff1"><label>1</label>
Program against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group, Catalan Institute of Oncology, Girona, Spain</aff>
<aff id="aff2"><label>2</label>
Girona Biomedical Research Institute (IDIBGI), Girona, Spain</aff>
<aff id="aff3"><label>3</label>
Cardiovascular Genetics Centre, Department of Medical Sciences, University of Girona, Girona, Spain</aff>
<aff id="aff4"><label>4</label>
Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain</aff>
<aff id="aff5"><label>5</label>
Medical Oncology, Catalan Institute of Oncology, Girona, Spain</aff>
<aff id="aff6"><label>6</label>
Department of Medical Sciences, Medical School University of Girona, Girona, Spain</aff>
<aff id="aff7"><label>7</label>
Hereditary Cancer Programme, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona, Spain</aff>
<aff id="aff8"><label>8</label>
Hereditary Cancer Programme, Catalan Institute of Oncology (ICO), Girona Biomedical Research Institute (IDIBGI), Girona, Spain</aff>
<aff id="aff9"><label>9</label>
Department of Anatomical Pathology, Dr. Josep Trueta Hospital of Girona, Girona, Spain</aff>
<aff id="aff10"><label>10</label>
Unit of Clinical Research, Catalan Institute of Oncology, Girona, Spain</aff>
<aff id="aff11"><label>11</label>
Institute of Research, Development and Innovation in Biotechnology of Elche (IDiBE) and Molecular and Cell Biology Institute (IBMC), Miguel Hernández University (UMH), Elche, Spain</aff>
</contrib-group>
<author-notes><fn fn-type="equal" id="F1"><label>*</label>
<p id="P1">Equal contribution</p>
</fn>
<corresp id="cor1"><bold>Correspondence to:</bold>
Javier A. Menendez; <bold>email:</bold>
jmenendez@iconcologia.net, jmenendez@idibgi.org</corresp>
<corresp id="cor2"><bold>Correspondence to:</bold>
José Antonio Encinar; <bold>email:</bold>
jant.encinar@umh.es</corresp>
</author-notes>
<pub-date pub-type="collection"><day>15</day>
<month>1</month>
<year>2020</year>
</pub-date>
<pub-date pub-type="epub"><day>04</day>
<month>1</month>
<year>2020</year>
</pub-date>
<volume>12</volume>
<issue>1</issue>
<fpage>8</fpage>
<lpage>34</lpage>
<history><date date-type="received"><day>09</day>
<month>8</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>23</day>
<month>12</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2020 Verdura et al.</copyright-statement>
<license specific-use="CC BY 3.0" xlink:href="http://creativecommons.org/licenses/by/3.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p>
</license>
</permissions>
<abstract><p>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 <italic>N</italic>
-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.</p>
</abstract>
<kwd-group kwd-group-type="author"><title>Keywords:</title>
<kwd>PD-L1</kwd>
<kwd>resveratrol</kwd>
<kwd>immunotherapy</kwd>
<kwd>T cells</kwd>
<kwd>glycosylation</kwd>
</kwd-group>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Espagne</li>
</country>
<region><li>Catalogne</li>
<li>Communauté de Madrid</li>
</region>
<settlement><li>Barcelone</li>
<li>Madrid</li>
</settlement>
</list>
<tree><country name="Espagne"><noRegion><name sortKey="Verdura, Sara" sort="Verdura, Sara" uniqKey="Verdura S" first="Sara" last="Verdura">Sara Verdura</name>
</noRegion>
<name sortKey="Bosch Barrera, Joaquim" sort="Bosch Barrera, Joaquim" uniqKey="Bosch Barrera J" first="Joaquim" last="Bosch-Barrera">Joaquim Bosch-Barrera</name>
<name sortKey="Bosch Barrera, Joaquim" sort="Bosch Barrera, Joaquim" uniqKey="Bosch Barrera J" first="Joaquim" last="Bosch-Barrera">Joaquim Bosch-Barrera</name>
<name sortKey="Bosch Barrera, Joaquim" sort="Bosch Barrera, Joaquim" uniqKey="Bosch Barrera J" first="Joaquim" last="Bosch-Barrera">Joaquim Bosch-Barrera</name>
<name sortKey="Brunet, Joan" sort="Brunet, Joan" uniqKey="Brunet J" first="Joan" last="Brunet">Joan Brunet</name>
<name sortKey="Brunet, Joan" sort="Brunet, Joan" uniqKey="Brunet J" first="Joan" last="Brunet">Joan Brunet</name>
<name sortKey="Brunet, Joan" sort="Brunet, Joan" uniqKey="Brunet J" first="Joan" last="Brunet">Joan Brunet</name>
<name sortKey="Brunet, Joan" sort="Brunet, Joan" uniqKey="Brunet J" first="Joan" last="Brunet">Joan Brunet</name>
<name sortKey="Cortada, Eric" sort="Cortada, Eric" uniqKey="Cortada E" first="Eric" last="Cortada">Eric Cortada</name>
<name sortKey="Cortada, Eric" sort="Cortada, Eric" uniqKey="Cortada E" first="Eric" last="Cortada">Eric Cortada</name>
<name sortKey="Cortada, Eric" sort="Cortada, Eric" uniqKey="Cortada E" first="Eric" last="Cortada">Eric Cortada</name>
<name sortKey="Cuyas, Elisabet" sort="Cuyas, Elisabet" uniqKey="Cuyas E" first="Elisabet" last="Cuyàs">Elisabet Cuyàs</name>
<name sortKey="Cuyas, Elisabet" sort="Cuyas, Elisabet" uniqKey="Cuyas E" first="Elisabet" last="Cuyàs">Elisabet Cuyàs</name>
<name sortKey="Encinar, Jose Antonio" sort="Encinar, Jose Antonio" uniqKey="Encinar J" first="José Antonio" last="Encinar">José Antonio Encinar</name>
<name sortKey="Lopez Bonet, Eugeni" sort="Lopez Bonet, Eugeni" uniqKey="Lopez Bonet E" first="Eugeni" last="Lopez-Bonet">Eugeni Lopez-Bonet</name>
<name sortKey="Martin Castillo, Bego A" sort="Martin Castillo, Bego A" uniqKey="Martin Castillo B" first="Bego A" last="Martin-Castillo">Bego A Martin-Castillo</name>
<name sortKey="Menendez, Javier A" sort="Menendez, Javier A" uniqKey="Menendez J" first="Javier A." last="Menendez">Javier A. Menendez</name>
<name sortKey="Menendez, Javier A" sort="Menendez, Javier A" uniqKey="Menendez J" first="Javier A." last="Menendez">Javier A. Menendez</name>
<name sortKey="Verdura, Sara" sort="Verdura, Sara" uniqKey="Verdura S" first="Sara" last="Verdura">Sara Verdura</name>
</country>
</tree>
</affiliations>
</record>
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