Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity02-13-2020
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.
Dr. Javier A. Menendez from the Program against Cancer Therapeutic Resistance (ProCURE), Metabolism and Cancer Group at the Catalan Institute of Oncology as well as the Girona Biomedical Research Institute (IDIBGI) and Dr. José Antonio Encinar from the Institute of Research, Development and Innovation in Biotechnology of Elche (IDiBE) and Molecular and Cell Biology Institute (IBMC), at Miguel Hernández University (UMH) said, "Unlike immunologically “hot” tumors such as lung cancer, melanoma, and bladder cancer, most breast carcinomas are not inherently immunogenic."
Correspondingly, the otherwise rare expression in most breast carcinomas of programmed death ligand-1 an archetypal immunosuppressive molecule on cancer cells that engages its receptor PD-1 on T-cells to suppress T-cell-mediated immune surveillance is markedly enriched in basal-like and HER2-positive tumors, thereby implying that PD-L1 confers a survival advantage in the tumor microenvironment of these specific breast cancer subtypes.
Figure 9. Resveratrol enhances antitumor T cell immunity by promoting abnormal glycosylation and dimerization of PD-L1. Post-translational modifications such as glycosylation, phosphorylation, palmitoylation or ubiquitination are essential for the folding, intracellular transport, and stabilization of the PD-L1 protein [41, 110–114]. PD-L1 is highly glycosylated, and N-linked glycosylation of PD-L1 critically maintains its protein stability and is required for its interaction with PD-1 to efficiently suppress T-cell activity. Recently, Bristol-Myers Squibb (BMS)-developed compounds with a common (2-methyl-4-biphenylyl)methanol scaffold have been reported to block the PD-1/PD-L1 interaction by interacting with the cavity formed by the two PD-L1 monomers and inducing the dimerization of PD-L1 [71–77]. Structural studies have revealed a dimeric protein complex with a single small molecule that stabilizes the dimer and thereby occludes the PD-1 interaction surface of PD-L1. We propose that RSV is a naturally occurring, double-strike PD-1/PD-L1 immune checkpoint inhibitor capable of directly blocking the enzymatic machinery in charge of the N-linked glycosylation of the nascent PD-L1 at the endoplasmic reticulum or directly binding to PD-L1 surfaces to induce PD-L1 dimerization and block PD-1 binding. This unforeseen ability of RSV to directly interfere with PD-L1 stability and trafficking impedes the correct targeting of PD-L1 to the cancer cell plasma membrane and ultimately elicits drastically enhanced cytotoxic T-lymphocyte immune-surveillance against tumor cells. These findings might illuminate new approaches to restore T-cell function by targeting the PD-1/PD-L1 immunologic checkpoint with natural polyphenols.
Indeed, the inhibitory nature of the metabolic interplay between tumor and immune cells in the TME supports its suitability as a target to overcome the immune escape of cancer cells and circumvent immunotherapy resistance.
Nonetheless, the appraisal of cancer cell-autonomous metabolic reprogramming as a bona fide driver of immune checkpoint signaling in tumor cells is a largely neglected area in cancer immunometabolism.
Here, the authors took advantage of the JIMT-1 cell line, a unique model of highly-aggressive basal-like/HER2-positive breast cancer naturally overexpressing the immunosuppressive molecule PD-L1 with 100% of the cells positive for PD-L1, to explore the potential regulatory effects of mechanistically diverse metabolism-targeting drugs on PD-L1.
The Menendez/Encinar Research Team concluded that the double-strike PD-1/PD-L1 immune checkpoint inhibitor-like behavior of RSV based on its ability to directly target PD-L1 either via key post-translational modifications such as N-linked glycosylation or via direct binding to PD-L1 to block PD-1 binding interferes with PD-L1 stability and trafficking, impedes the correct targeting of PD-L1 to the cancer cell plasma membrane, and lastly elicits considerably enhanced cytotoxic T-lymphocyte immune-surveillance against tumor cells.
Full Text - https://doi.org/10.18632/aging.102646
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