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

Abstract

Simple Summary Over the last decade, immunotherapies using antibodies targeting the programmed cell death 1 (PD-1) checkpoint or its ligand, programmed death ligand 1 (PD-L1), have emerged as promising therapeutic strategies against cancer. However, some current limitations include a relatively low rate of “responders”, the high cost of the treatment, and a rare risk of hyper-progression. Currently, the main challenge is, therefore, to improve these therapies, for instance, by using combined approaches. Here, we summarize the accumulating evidence that resveratrol (RSV) plays a role in the modulation of the PD-1/PD-L1 axis in cancer cells, suggesting the potential of therapeutic strategies combining RSV with PD-L1 or anti-PD-1 inhibitors. We then discuss the therapeutic potential of polyphenols such as RSV to be used in combination with PD-L1 or PD-1 inhibitors for the management of cancer patients. 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.