Priority Research Paper Volume 12, Issue 1 pp 8—34

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.