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

Aging (Albany NY). 2020 Jan 4;12(1):8-34. doi: 10.18632/aging.102646. Epub 2020 Jan 4.


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.

Keywords: PD-L1; T cells; glycosylation; immunotherapy; resveratrol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • 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*


  • Antineoplastic Agents
  • B7-H1 Antigen
  • CD274 protein, human
  • Carrier Proteins
  • Resveratrol