Abstract
BackgroundThe PD-L1/PD-1 pathway blockade-mediated immune therapy has shown promising efficacy in the treatment of multiple cancers including melanoma. The present study investigated the effects of the flavonoid apigenin on the PD-L1 expression and the tumorigenesis of melanoma.MethodsThe influence of flavonoids on melanoma cell growth and apoptosis was investigated using cell proliferation and flow cytometric analyses. The differential IFN-γ-induced PD-L1 expression and STAT1 activation were examined in curcumin and apigenin-treated melanoma cells using immunoblotting or immunofluorescence assays. The effects of flavonoid treatment on melanoma sensitivity towards T cells were investigated using Jurkat cell killing, cytotoxicity, cell viability, and IL-2 secretion assays. Melanoma xenograft mouse model was used to assess the impact of flavonoids on tumorigenesis in vivo. Human peripheral blood mononuclear cells were used to examine the influence of flavonoids on PD-L1 expression in dendritic cells and cytotoxicity of cocultured cytokine-induced killer cells by cell killing assays.ResultsCurcumin and apigenin showed growth-suppressive and pro-apoptotic effects on melanoma cells. The IFN-γ-induced PD-L1 upregulation was significantly inhibited by flavonoids, especially apigenin, with correlated reductions in STAT1 phosphorylation. Apigenin-treated A375 cells exhibited increased sensitivity towards T cell-mediated killing. Apigenin also strongly inhibited A375 melanoma xenograft growth in vivo, with enhanced T cell infiltration into tumor tissues. PD-L1 expression in dendritic cells was reduced by apigenin, which potentiated the cytotoxicity of cocultured cytokine-induced killer cells against melanoma cells.ConclusionsApigenin restricted melanoma growth through multiple mechanisms, among which its suppression of PD-L1 expression exerted a dual effect via regulating both tumor and antigen presenting cells. Our findings provide novel insights into the anticancer effects of apigenin and might have potential clinical implications.
Highlights
The Programmed cell death ligand-1 (PD-L1)/programmed cell death-1 (PD-1) pathway blockade-mediated immune therapy has shown promising efficacy in the treatment of multiple cancers including melanoma
In the following flow cytometric analyses of cell cycle distribution, both curcumin and apigenin treatment led to cell cycle blockage at G2/M phases, with concurrent decreased cell numbers distributed at G1 and S phases in A375, A2058, and RPMI-7951 cells (Fig. 1g-i)
Given that apigenin positively regulated the levels of CD4+ and CD8+ T cells in the melanoma-bearing mouse hosts and this flavonoid was capable of inhibiting the activation of signal transducer and activator of transcription 1 (STAT1) following IFN-γ stimulation, we investigated whether apigenin treatment could influence the PD-L1 expression levels in Dendritic cell (DC) to regulate T cell immunity against melanoma cells
Summary
The PD-L1/PD-1 pathway blockade-mediated immune therapy has shown promising efficacy in the treatment of multiple cancers including melanoma. Melanoma is a common type of skin cancer that is frequently associated with poor clinical outcomes. Taking its advantages of high immunogenicity and the abundance of adjacent immune cells, melanoma has become a successful leading example of immune checkpoint blockade-based immunotherapy, proving the PD-1/PD-L1 pathway as a top therapeutic target in this skin malignancy [6, 7]. Monoclonal antibodies targeting PD-1, such as nivolumab and pembrolizumab, and the PD-L1 antibody atezolizumab effectively block the PD-1/PD-L1 interaction, representing a successful approach of immune checkpoint blockade that has received multiple FDA approvals in cancer treatment [10, 11]
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