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.