Resveratrol Induces PD-L1 Expression Through Snail-driven Activation of Wnt Pathway in Lung Cancer Cells

Purpose: Recent clinical trials with agents targeting immune checkpoint pathway have emerged as an important therapeutic approach for a broad range of cancer types. Resveratrol has been shown to possess cancer preventive and therapeutic effects and has potential to be chemotherapeutic agent/adjuvant. Here, we assessed the effect of resveratrol on immune checkpoint pathways.

Methods: The expression patterns of Wnt components and PD-L1 were examined by Western blot, Chromatin immunoprecipitation (ChIP) was used for analysis of DNA-protein interaction, the promoter activity was determined by luciferase reporter assay, apoptosis was analyzed by flow cytometry and the ability of the resveratrol to modulate T cell function was assessed in a co-culture system.

Results: Although the dose-, and cell-type dependent effects of resveratrol on PD-L1 expression have been reported, we show here that resveratrol dose-dependently upregulates PD-L1 expression at the range of pharmacologic-achievable concentrations in lung cancer cells and that is essential for suppression of T-cell-mediated immune response. We also found that Wnt pathway is critical for mediating resveratrol-induced PD-L1 upregulation. Mechanistically, resveratrol activates SirT1 deacetylase to deacetylate and stabilize transcriptional factor Snail. Snail in turn inhibits transcription of Axin2, which leads in disassembly of destruction complex and enhanced binding of β-catenin/TCF to PD-L1 promoter.

Conclusion: We conclude that resveratrol is capable to suppress anti-tumor immunity by controlling mainly PD-L1 expression. This finding will extend the understanding of resveratrol in regulation of tumor immunity and is relevant to the debate on resveratrol supplements for lung cancer patients.