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.
Highlights
Phytochemicals are bioactive compounds that are naturally produced in plants such as fruits and vegetables
A recent study showed that the triple blockade of lymphocyte activation gene-3 (LAG-3), programmed cell death receptor 1 (PD-1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) significantly enhanced antitumor immunity compared with the use of a single anti-PD-1 Ab, resulting in increased cytotoxic T cell levels and reduced Tregs and myeloid-derived suppressor cells (MDSCs) in an ovarian cancer mouse model [66]
The treatment of Caffeic Acid Phenethyl Ester (CAPE), as an inhibitor of NF-κB, remarkably decreased the expression of programmed death-ligand 1 (PD-L1) in EpsteinBarr virus (EBV)-positive nasopharyngeal carcinoma (NPC) cell line and latent membrane protein 1 (LMP1)-overexpressed normal nasopharyngeal epithelial cell line [121]. These results indicated a therapeutic potential of CAPE for supportive use with Immune checkpoint inhibitor (ICI) treatment by suppressing LMP1-induced PD-L1 expression through inhibiting
Summary
Phytochemicals are bioactive compounds that are naturally produced in plants such as fruits and vegetables. The tumor-suppressive mechanisms of phytochemicals include disrupting redox balance of cancer cells, inhibiting proliferation, inducing cell cycle arrest, and apoptosis and boosting anti-cancer immunity. These biomodulatory effects of phytochemicals lead to decreased cancer cell growth, progression, and chemotherapy resistance. The activities of PD-1 and its ligand PD-L1 are responsible for reducing activation, proliferation, and cytokine secretion of T cells in TME, resulting in decreased anti-tumor immune responses [20]. In TME, tumor cells express PD-L1 as an escape signal from the anti-tumor immune activity. Many recent studies suggest that other notorious oncogenic signaling pathways, such as WNT, NF-κB, and Hedgehog pathways, may be involved in PD-L1 expression in cancer cells [20]
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