Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity
Por:
Verdura, S, Cuyas, E, Cortada, E, Brunet, J, Lopez-Bonet, E, Martin-Castillo, B, Bosch-Barrera, J, Encinar, J and Menendez, J
Publicada:
15 ene 2020
Resumen:
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.
Filiaciones:
Verdura, S:
Catalan Inst Oncol, Metab & Canc Grp, Program Canc Therapeut Resistance ProCURE, Girona, Spain
Girona Biomed Res Inst IDIBGI, Girona, Spain
Cuyas, E:
Catalan Inst Oncol, Metab & Canc Grp, Program Canc Therapeut Resistance ProCURE, Girona, Spain
Girona Biomed Res Inst IDIBGI, Girona, Spain
Cortada, E:
Girona Biomed Res Inst IDIBGI, Girona, Spain
Univ Girona, Cardiovasc Genet Ctr, Dept Med Sci, Girona, Spain
Ctr Invest Biomed Red Enfermedades Cardiovasc CIB, Madrid, Spain
Brunet, J:
Catalan Inst Oncol, Med Oncol, Girona, Spain
Univ Girona, Dept Med Sci, Med Sch, Girona, Spain
Hosp Llobregat, Catalan Inst Oncol ICO, Bellvitge Inst Biomed Res IDIBELL, Hereditary Canc Programme, Barcelona, Spain
Girona Biomed Res Inst IDIBGI, Catalan Inst Oncol ICO, Hereditary Canc Programme, Girona, Spain
Lopez-Bonet, E:
Dr Josep Trueta Hosp Girona, Dept Anat Pathol, Girona, Spain
Martin-Castillo, B:
Catalan Inst Oncol, Unit Clin Res, Girona, Spain
Bosch-Barrera, J:
Girona Biomed Res Inst IDIBGI, Girona, Spain
Catalan Inst Oncol, Med Oncol, Girona, Spain
Univ Girona, Dept Med Sci, Med Sch, Girona, Spain
:
Miguel Hernandez Univ UMH, Inst Res Dev & Innovat Biotechnol Elche IDiBE, Elche, Spain
Miguel Hernandez Univ UMH, Mol & Cell Biol Inst IBMC, Elche, Spain
Menendez, J:
Catalan Inst Oncol, Metab & Canc Grp, Program Canc Therapeut Resistance ProCURE, Girona, Spain
Girona Biomed Res Inst IDIBGI, Girona, Spain
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