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Review
. 2021 Jul 27;11(8):1107.
doi: 10.3390/biom11081107.

Phytochemicals in Cancer Immune Checkpoint Inhibitor Therapy

Juwon Lee  1   2 , Youngjin Han  1   3 , Wenyu Wang  1   4 , HyunA Jo  1   2 , Heeyeon Kim  1   2 , Soochi Kim  5 , Kyung-Min Yang  6 , Seong-Jin Kim  6   7   8 , Danny N Dhanasekaran  9   10 , Yong Sang Song  1   2   4   11
Affiliations
Review

Phytochemicals in Cancer Immune Checkpoint Inhibitor Therapy

Juwon Lee et al. Biomolecules. .

Abstract

The interaction of immune checkpoint molecules in the tumor microenvironment reduces the anti-tumor immune response by suppressing the recognition of T cells to tumor cells. Immune checkpoint inhibitor (ICI) therapy is emerging as a promising therapeutic option for cancer treatment. However, modulating the immune system with ICIs still faces obstacles with severe immunogenic side effects and a lack of response against many cancer types. Plant-derived natural compounds offer regulation on various signaling cascades and have been applied for the treatment of multiple diseases, including cancer. Accumulated evidence provides the possibility of efficacy of phytochemicals in combinational with other therapeutic agents of ICIs, effectively modulating immune checkpoint-related signaling molecules. Recently, several phytochemicals have been reported to show the modulatory effects of immune checkpoints in various cancers in in vivo or in vitro models. This review summarizes druggable immune checkpoints and their regulatory factors. In addition, phytochemicals that are capable of suppressing PD-1/PD-L1 binding, the best-studied target of ICI therapy, were comprehensively summarized and classified according to chemical structure subgroups. It may help extend further research on phytochemicals as candidates of combinational adjuvants. Future clinical trials may validate the synergetic effects of preclinically investigated phytochemicals with ICI therapy.

Keywords: PD-1; PD-L1; cancer immunotherapy; immune checkpoint; phytochemical.

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Conflict of interest statement

S.-J.K. has personal financial interests as a shareholder in MedPacto Inc. All other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Various phytochemicals and their representative sources may modulate anti-PD-1/PD-L1 ICI therapy. Isolated phytochemicals and their sources are shown according to the structural subgroups. Flavonoid polyphenolic compounds include EGCG, icaritin, apigenin, luteolin, baicalein, silymarin, anthocyanin, C3G, and hesperidin. Non-flavonoid polyphenolic compounds include curcumin, gallic acid, polydatin, resveratrol, piceatannol, emodin, and CAPE. Terpenes include lycopene, cryptotanshinone, β-elemene, triptolide, fraxinellone, saponins, and cannabidiol. Others include sulforaphane and camptothecin. EGCG: epigallocatechin gallate; C3G: Cyanidin 3-O-glucoside; CAPE: caffeic acid phenethyl ester.
Figure 2
Figure 2
Various types of immune checkpoint receptors and ligands and their regulatory factors. Interactions of immune checkpoint receptors with ligand and their intra- and extracellular regulatory factors are indicated by arrow points. PD-1: programmed death-ligand 1; PD-L1: programmed death-receptor 1; MHC-II: major histocompatibility complex class II; CTLA-4: cytotoxic T lymphocyte antigen 4; VISTA: V-domain Ig suppressor of T cell activation; LAG-3: lymphocyte activation gene-3; TCR: T cell receptor; TIM-3: T cell immunoglobulin and mucin-domain containing-3; IRF9: IFN regulatory factor 9.
Figure 3
Figure 3
Classification of phytochemicals modulating activity of ICI according to chemical structures. Listed compounds are classified into the families of flavonoids, non-flavonoids, terpenes, and others. Flavonoids include EGCG, apigenin, luteolin, silymarin, anthocyanins, quercetin, C3G, icaritin, baicalein, and hesperidin. Non-flavonoids include curcumin, resveratrol, piceatannol, polydatin, CAPE, gallic acid, and emodin. Terpenes include lycopene, β-elemene, fraxinellone, cannabidiol, cryptotanshinone, triptolide, ginsenoside Rg3, ginsenoside Rk1, ginsenoside Rh2, platycodin D, diosgenin, and panaxadiol. Others include sulforaphane and camptothecin. EGCG: epigallocatechin gallate; C3G: cyanidin 3-O-glucoside; CAPE: caffeic acid phenethyl ester.
Figure 4
Figure 4
Schematic representation of signaling pathways regulating PD-L1 expression in cancer cell, dendritic cell (DC), and T cell targeted by bioactive phytochemicals. Phytochemicals modulate therapeutic effects of ICI and expression of PD-L1 through the regulation of multiple signaling pathways, including IFN-γ/JAK/STAT, EGFR/Akt, and TNF-α/NF-κB signaling pathways. Many phytochemicals regulate PD-L1 expression by targeting pathways related to PD-L1 transcription and certain phytochemicals inhibit glycosylation of PD-L1 protein or PD-1/PD-L1 binding. Phytochemicals are listed in white or grey boxes. Arrows indicate activations; blunt-ended lines indicate inhibitory effects; dotted arrows indicate translocations.
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References

    1. Yeum K.-J., Russell R.M. Biological Functions of Plant Pigment Phytochemicals in Humans. In: Laher I., editor. Systems Biology of Free Radicals and Antioxidants. Springer; Berlin/Heidelberg, Germany: 2014. pp. 4023–4045. - DOI
    1. Achilonu M.C., Umesiobi D.O. Bioactive Phytochemicals: Bioactivity, Sources, Preparations, and/or Modifications via Silver Tetrafluoroborate Mediation. J. Chem. 2015;2015:1–22. doi: 10.1155/2015/629085. - DOI
    1. Zubair H., Khan M.A., Anand S., Srivastava S.K., Singh S., Singh A.P. Modulation of the tumor microenvironment by natural agents: Implications for cancer prevention and therapy. Semin. Cancer Biol. 2020 doi: 10.1016/j.semcancer.2020.05.009. - DOI - PMC - PubMed
    1. Giannone G., Ghisoni E., Genta S., Scotto G., Tuninetti V., Turinetto M., Valabrega G. Immuno-Metabolism and Microenvironment in Cancer: Key Players for Immunotherapy. Int. J. Mol. Sci. 2020;21:4414. doi: 10.3390/ijms21124414. - DOI - PMC - PubMed
    1. Cybulska-Stopa B., Rogala P., Czarnecka A.M., Ługowska I., Teterycz P., Galus L., Rajczykowski M., Dawidowska A., Piejko K., Suwiński R., et al. Efficacy of ipilimumab after anti-PD-1 therapy in sequential treatment of metastatic melanoma patients -Real world evidence. Adv. Med. Sci. 2020;65:316–323. doi: 10.1016/j.advms.2020.05.005. - DOI - PubMed

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