Abstract
The interaction of programmed cell death-1 (PD-1) and its ligand programed cell death-1 ligand (PD-L1) is a major focus of recent immune oncology therapy efforts. The expression of PD-1 on T lymphocytes and its subsequent interaction with PD-L1, either from antigen presenting or tumor cells, will result in apoptosis-dependent inactivation of the T lymphocytes. This interaction plays an integral role in tumor immunology, specifically augmenting immune evasion. Relatively little is known about the regulation of PD-L1 in either the tumor or normal environment. We investigated the ability of natural dietary compounds to induce PD-L1 expression on normal epithelial cells and various cancer cell lines. These molecules have been evolutionary selected to control inflammation and cancer cell transformation and progression, understanding their mechanism of action could be important to understanding how this system works. Using flow cytometry and immunohistochemistry, we focused our studies on resveratrol and its metabolite piceatannol, key phytochemicals extracted from grapes, after an initial screen of various natural products. Experimental data showed that both compounds can individually up-regulate the expression of PD-L1 on tumor cell lines and normal epithelial cells, by an IFN-γ-independent mechanism. PD-L1 induction by both of these compounds was higher in tumor than in normal epithelium, suggesting greater significance in tumor regulation than inflammation. Additionally, the combination of resveratrol and piceatannol acted synergistically, leading to a significantly greater induction of PD-L1 expression across multiple tumor indications. Understanding whether resveratrol and piceatannol use a common signaling pathway to induce PD-L1 expression in tumor cells, was critical to understand the synergistic induction observed. Studies utilizing specific inhibition of IKK phosphorylation were accompanied by a significant reduction in the ability to induce PD-L1 expression on tumor cells, either as single agents or in combination. These results are consistent with the hypothesis that induction of PD-L1 by resveratrol or piceatannol, or their combination involves molecular determinants down-stream of NF-kB signaling.
Citation Format: Justin P. Lucas, Joseph M. Wu, TzeChen Hsieh, Zbigniew Darzynkiewicz, Halina Dorota Halicka-Ambroziak. Resveratrol and piceatannol synergistically induce PDL1 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2654. doi:10.1158/1538-7445.AM2017-2654
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