Development of natural products for anti-PD-1/PD-L1 immunotherapy against cancer

https://doi.org/10.1016/j.jep.2021.114370Get rights and content

Abstract

Ethnopharmacological relevance

The programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint is one of the most promising therapeutic targets for cancer immunotherapy, but several challenges remain in current anti-PD-1/PD-L1 therapy. Natural products, mainly derived from traditional medicine, could improve and expand anti-PD-1/PD-L1 therapy because of their advantages such as large diversity and multi-target effects.

Aim of the study

This review summarize natural products, raw extracts, and traditional medicines with pharmacological effects associated with the PD-1/PD-L1 axis, particularly PD-L1.

Materials and methods

Electronic literature databases, including Web of Science, PubMed, and ScienceDirect, and online drugs and chemicals databases, including DrugBank, ZINC, PubChem, STITCH, and CTD, were searched without date limitation by February 2021. ‘Natural product or herb or herbal plant or traditional medicine’ and ‘PD-L1’ and ‘Cancer immunotherapy’ were used as the search keywords. Among 112 articles identified in database searching, 54 articles are full text articles, reporting in silico, in vitro, in vivo and clinical trials. 68 articles included are review articles and grey literature such as thesis and congress abstracts.

Results

Several natural products and traditional medicines have exhibited diverse and multi-functional effects including direct blockade of PD-1/PD-L1 interactions, modulation of PD-L1 expression, and cooperation with PD-1/PD-L1 inhibitors.

Conclusion

Natural products and traditional medicines can facilitate the development of more effective and acceptable diverse strategies for anti-PD-1/PD-L1 therapy, but further exploration of natural products and pharmaceutical techniques is required.

Introduction

Programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) have received great interest in anti-cancer research because of their prominent roles in tumor immune escape and proven clinical significance in cancer treatment (Guo, L. et al., 2020; Sun et al., 2018). Because many types of tumor cells exploit the PD-1/PD-L1 axis to escape immunosurveillance and inhibit attack by immune cells such as cytotoxic T lymphocytes (CTLs), blockage of this immune checkpoint allows the immune system to reverse immunosuppressive states and improve the killing of tumor cells (Wu et al., 2021). Indeed, antibodies targeting PD-1 or PD-L1 have been proven effective against a wide range of tumor types, and they have lower toxicity and longer-lasting responses than other immunotherapies (Ai et al., 2020). Although PD-1/PD-L1 antibodies have provided breakthroughs in cancer immunotherapy, their clinical efficacy is often lower than expected in many cases due to the complexity of tumor immune escape and some clinical troubles (Kumar et al., 2020; Li, J.X. et al., 2019; Sangro et al., 2020; Sun et al., 2018; Wu et al., 2021). These problems have prompted the development of more effective, flexible, safe, and economically feasible drugs targeting the PD-1/PD-L1 axis (Barroso-Sousa and Tolaney, 2020; Gong et al., 2018; Wu et al., 2021).

Natural products have innumerable diversity, and most of them are derived from herbal plants have been used long in traditional medicine (Shang et al., 2018; Song et al., 2018). Therefore, they could provide opportunities to resolve challenges in recent anti-PD-1/PD-L1 therapy as drug or lead compounds or as cooperative or complementary agents. Based on current understanding of the PD-1/PD-L1 immune checkpoint, we have summarized natural products with pharmacological effects associated with the PD-1/PD-L1 axis, particularly PD-L1, as well as raw extracts and traditional medicines with potential for natural product development.

Section snippets

PD-1/PD-L1 immune checkpoint as an anti-cancer target

Under normal conditions, the body's immune system prevents autoimmune reactions and modulates excess immune activity through a series of immune checkpoints, thereby maintaining immune homeostasis (Deng et al., 2020; Ohue and Nishikawa, 2019; Sebastiani et al., 2019). However, malignant cells can exploit these checkpoints in some cases to prohibit immune responses against tumors, thereby achieving immune escape and immortalization (Pardoll, 2012). Notably, PD-1/PD-L1 is a well-known immune

Natural products targeting the PD-1/PD-L1 axis

Natural products can target PD-1/PD-L1 axis via several strategies, including direct blockade of the PD-1 and PD-L1 interaction, suppression of PD-1/PD-L1 levels in tumors, and combination treatment (Fig. 1).

Conclusion

PD-1/PD-L1 immune checkpoint inhibition has been already known as a powerful therapeutic strategy against cancer. PD-1/PD-L1 antibodies have achieved remarkable success for treating a wide range of malignancies and contributed to revolutionary advances in cancer treatment. However, antibody drugs have several problems such as the poor permeability into tumor tissues, severe immune-related adverse reactions, and the need for intravenous administration. Moreover, in some case, its clinical

Author contributions

Myong Hak Ri: Writing-review & editing. Juan Ma and Xuejun Jin: Visualization, Writing-review & editing.

Declaration of competing interest

The authors declare that there are no financial conflicts of interest in regard to this work.

Acknowledgments

This work was partially supported by National Natural Science Foundation of China, No. 81660608 and 81760657.

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