PD-1/PD-L1 Checkpoints and Resveratrol: A Controversial New Way for a Therapeutic Strategy

Abstract

Immune checkpoints refer to a range of immunoregulatory molecules that modulate the immune response. For example, proteins expressed at the surface of T-cells (including PD-1 and CTLA-4) and their ligands (PD-L1 and B7-1/B7-2, respectively), expressed by cancer cells and antigen-presenting cells, are needed to prevent excessive immune responses. However, they dampen anti-tumor immunity by limiting T-cell activity, making them promising therapeutic targets in cancer. Although immunotherapies using checkpoint blocking/neutralizing antibodies targeting PD-L1 or PD-1 have proven their superiority over conventional chemotherapies or targeted therapies by enhancing T-cell-mediated anti-tumor immunity, some limitations have emerged. These include a relatively low rate of "responders" (<50%; irrespective of cancer type), the high cost of injections, and a rare risk of hyper-progression. For clinicians, the current challenge is thus to improve the existing therapies, potentially through combinatory approaches. Polyphenols such as resveratrol (RSV), a trihydroxystilbene found in various plants and an adjuvant in numerous nutraceuticals, have been proposed as potential therapeutic targets. Beyond its well-known pleiotropic effects, RSV affects PD-L1 and PD-1 expression as well as PD-L1 subcellular localization and post-translational modifications, which we review here. We also summarize the consequences of PD-1/PD-L1 signaling, the modalities of their blockade in the context of cancer, and the current status and limitations of these immunotherapies. Finally, we discuss their potential use in combination with chemotherapies, and, using RSV as a model, we propose polyphenols as adjuvants to enhance the efficacy of anti-PD-1/anti-PD-L1 immunotherapies.

Keywords: PD-1; PD-L1; immunotherapy; polyphenols; resveratrol.

Figure 1

RSV alters N-glycosylation to disrupt PD-1/PD-L1 interaction. PD-L1 is composed of a transmembrane region (TM domain) and two extracellular domains, the IgC-like and IgV-like domains. The short intracytoplasmic domain (ICD domain) of PD-L1 is responsible for the triggering of the signaling pathways inside cells. N-glycosylation is a major post-translational modification of PD-L1 that is crucial for its stability (prevention of PD-L1 degradation through GSK-3β-mediated 26S proteasome), intracellular trafficking, and functions (protein–protein interactions). Four glycosylation sites of asparagine residues (G) span within the IgV-like (1 site, N35) and IgC-like domains (3 sites of glycosylation, N192, N200, and N219). There is a ≈17 kDa shift in PD-L1 molecular weight between its non- (33 kDa) and N-glycosylated form (50 kDa). RSV interacts with and blocks α-glucosidase/α-mannosidase in tumoral cells and prevents glyco-PD-L1-processing, which, in turn, promotes the retention of the abnormally glycosylated form of PD-L1 in the endoplasmic reticulum. Ig-V, immunoglobulin variable; IgC, immunoglobulin constant; SER, smooth endoplasmic reticulum; RER, rough endoplasmic reticulum; TM, transmembrane; ICD, intracellular domain.

Figure 2

RSV used in combination with piceatannol leads to a synergistic induction of NF-kB expression and increases the translocation and nuclear accumulation of NF-kB p50 and p65 subunit in tumor cells. Activated NF-kB pathways then induce PD-L1 gene transcription by the binding of the p50 and p65 subunits to its promoter and can also regulate PD-L1 post-transcriptionally.