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

• Published in: Aging (Albany, NY.) NY.), 2020-01, Vol.12 (1), p.8-34
• Main Authors: Verdura, Sara, Cuyàs, Elisabet, Cortada, Eric, Brunet, Joan, Lopez-Bonet, Eugeni, Martin-Castillo, Begoña, Bosch-Barrera, Joaquim, Encinar, José Antonio, Menendez, Javier A
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; B7-H1 Antigen - chemistry; B7-H1 Antigen - metabolism; Carrier Proteins; Glycosylation - drug effects; Humans; Immunomodulation - drug effects; Models, Biological; Models, Molecular; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; Priority Research Paper; Protein Binding; Protein Multimerization - drug effects; Resveratrol - chemistry; Resveratrol - pharmacology; Signal Transduction - drug effects; Structure-Activity Relationship; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism
• ISSN: 1945-4589; 1945-4589
• DOI: 10.18632/aging.102646

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 -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.