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Cited by 177Cancer Immunotherapy and BiomarkersFlavonoids in Medical ResearchImmunotherapy and Immune Responses

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Apigenin suppresses PD-L1 expression in melanoma and host dendritic cells to elicit synergistic therapeutic effects

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Xu, Lu, Zhang, Yang, Tian, Kang, Chen, Xi, Zhang, Rongxin, Mu, Xindi, Wu, Yueguang, Wang, Duchuang, Wang, Shanshan, Liu, Fang, Wang, Taishu, Zhang, Jinrui, Liu, Shuyan, Zhang, Yingqiu, Tu, Caixia, Liu, Han·2018·Journal of Experimental & Clinical Cancer Research
DOI 10.1186/s13046-018-0929-6PMC PMC6206930
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Abstract

BACKGROUND: The 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. METHODS: The 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. RESULTS: Curcumin 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. CONCLUSIONS: Apigenin 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.

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Fig. 1 Apigenin and curcumin induce cell cycle blockage to inhibit melanoma cell growth. a-f A375, A2058, and RPMI-7951 melanoma cells were treated with apigenin or curcumin at various concentrations for 24 h and cell viability was detected by MTT assays. g-i indicated melanoma cells were treated with DMSO as control, curcumin (CCM, 25 μM), or apigenin (APG, 30 μM) for 24 h and cell cycle distribution was analyzed by flow cytometry. The column charts on the right show the quantitation of cells distributed at each stage in percentage. j-k primary melanocytes were treated with curcumin and apigenin at indicated concentrations for 24 h and cell viability was measured by MTT assays. Data were presented as the mean ± S.D. from three independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001
Fig. 1 Apigenin and curcumin induce cell cycle blockage to inhibit melanoma cell growth. a-f A375, A2058, and RPMI-7951 melanoma cells were treated with apigenin or curcumin at various concentrations for 24 h and cell viability was detected by MTT assays. g-i indicated melanoma cells were treated with DMSO as control, curcumin (CCM, 25 μM), or apigenin (APG, 30 μM) for 24 h and cell cycle distribution was analyzed by flow cytometry. The column charts on the right show the quantitation of cells distributed at each stage in percentage. j-k primary melanocytes were treated with curcumin and apigenin at indicated concentrations for 24 h and cell viability was measured by MTT assays. Data were presented as the mean ± S.D. from three independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001CC BY · PubMed Central
Fig. 2 Apigenin and curcumin induce apoptosis in melanoma cells. a A375, A2058, and RPMI-7951 cells were treated with DMSO (control), curcumin (25 μM), or apigenin (30 μM) for 24 h before stained with Hoechst 33342. More than 200 cells were counted from 3 random views and percentages for apoptotic cells were shown in (b). Scale bar = 50 μm. c melanoma cells were stained with Annexin V and PI before flow cytometric analysis following 24 h treatment with DMSO, curcumin (25 μM), or apigenin (30 μM). d quantitation data of apoptosis from (c). e A375, A2058, and RPMI-7951 were treated as mentioned above and cleaved PARP was detected by Western blot analysis. GAPDH was shown as a loading control. All experiments were performed with 3 biological repeats. Error bars represent S.D. *P < 0.05, **P < 0.01, and ***P < 0.001
Fig. 2 Apigenin and curcumin induce apoptosis in melanoma cells. a A375, A2058, and RPMI-7951 cells were treated with DMSO (control), curcumin (25 μM), or apigenin (30 μM) for 24 h before stained with Hoechst 33342. More than 200 cells were counted from 3 random views and percentages for apoptotic cells were shown in (b). Scale bar = 50 μm. c melanoma cells were stained with Annexin V and PI before flow cytometric analysis following 24 h treatment with DMSO, curcumin (25 μM), or apigenin (30 μM). d quantitation data of apoptosis from (c). e A375, A2058, and RPMI-7951 were treated as mentioned above and cleaved PARP was detected by Western blot analysis. GAPDH was shown as a loading control. All experiments were performed with 3 biological repeats. Error bars represent S.D. *P < 0.05, **P < 0.01, and ***P < 0.001CC BY · PubMed Central
Fig. 3 Apigenin and curcumin suppress IFN-γ-induced PD-L1 expression in human melanoma cells. a-c indicated melanoma cells were pretreated with DMSO, curcumin (25 μM), or apigenin (30 μM) for 4 h and then treated with IFN-γ (10 ng/ml) for 24 h. Cells were lysed and PD-L1 expression was detected by Western blotting using a PD-L1 antibody. GAPDH was used as a loading control. Column charts below show quantitation data of relative PD-L1 expression. Error bars represent the mean ± S.D. (n = 3, *P < 0.05 and **P < 0.01). d and e cells were treated as described above and processed for immunofluorescence analysis. Representative micrographs show PD-L1 staining from different groups with same intensity settings on a fluorescent microscope (Olympus, Japan). DAPI stains nucleus. Scale bar = 25 μm. f and g, A375 and A2058 cells were treated as described above, and cell surface PD-L1 expression was determined by flow cytometry
Fig. 3 Apigenin and curcumin suppress IFN-γ-induced PD-L1 expression in human melanoma cells. a-c indicated melanoma cells were pretreated with DMSO, curcumin (25 μM), or apigenin (30 μM) for 4 h and then treated with IFN-γ (10 ng/ml) for 24 h. Cells were lysed and PD-L1 expression was detected by Western blotting using a PD-L1 antibody. GAPDH was used as a loading control. Column charts below show quantitation data of relative PD-L1 expression. Error bars represent the mean ± S.D. (n = 3, *P < 0.05 and **P < 0.01). d and e cells were treated as described above and processed for immunofluorescence analysis. Representative micrographs show PD-L1 staining from different groups with same intensity settings on a fluorescent microscope (Olympus, Japan). DAPI stains nucleus. Scale bar = 25 μm. f and g, A375 and A2058 cells were treated as described above, and cell surface PD-L1 expression was determined by flow cytometryCC BY · PubMed Central
Fig. 4 Apigenin and curcumin attenuate IFN-γ-induced STAT1 phosphorylation in human melanoma cells. a-c, A375, A2058, and RPMI-7951 cells were incubated with DMSO, curcumin (25 μM), or apigenin (30 μM) for 4 h and then treated with IFN-γ (10 ng/ml) for indicated times. The levels of STAT1 phosphorylation at Tyr701 and total STAT1 were detected by Western blot analysis. GAPDH was used as a loading control. Line charts on the right show the quantitation data of pSTAT1 by comparing to the levels with 1 min IFN-γ stimulation from the control group (100%) of each cell line. Data were presented as the mean ± S.D. from three independent experiments
Fig. 4 Apigenin and curcumin attenuate IFN-γ-induced STAT1 phosphorylation in human melanoma cells. a-c, A375, A2058, and RPMI-7951 cells were incubated with DMSO, curcumin (25 μM), or apigenin (30 μM) for 4 h and then treated with IFN-γ (10 ng/ml) for indicated times. The levels of STAT1 phosphorylation at Tyr701 and total STAT1 were detected by Western blot analysis. GAPDH was used as a loading control. Line charts on the right show the quantitation data of pSTAT1 by comparing to the levels with 1 min IFN-γ stimulation from the control group (100%) of each cell line. Data were presented as the mean ± S.D. from three independent experimentsCC BY · PubMed Central
Fig. 5 The effects of flavonoids in Jurkat cell-mediated A375 killing assays. a A375 cells were treated with DMSO, curcumin, or apigenin in the presence of IFN-γ (10 ng/ml) for 24 h, before cocultured with activated PD-1 expressing Jurkat T cells with effector to target ratios of 10:1 and 20:1. After 72 h of incubation, surviving tumor cells in 12-well plate were stained by crystal violet and imaged. Relative intensities of surviving cells are shown in the right chart, with IFN-γ-treated sample (10:1 group) set to be 100%. b and c cell killing assays were set up as described above in a 96-well plate. The cytotoxicity of T cells against A375 cells at an effector to target ratio of 10:1 was analyzed using an LDH detection assay kit (percentages calculated as per kit instruction) and remaining cell viability was assessed by MTT assay (control sample set to be 100%). d secreted IL-2 from Jurkat-mediated A375 killing assays was measured using supernatants from cocultures by an IL-2 ELISA kit. Data are represented as mean ± S.D. (n = 3, *P < 0.05 and **P < 0.01)
Fig. 5 The effects of flavonoids in Jurkat cell-mediated A375 killing assays. a A375 cells were treated with DMSO, curcumin, or apigenin in the presence of IFN-γ (10 ng/ml) for 24 h, before cocultured with activated PD-1 expressing Jurkat T cells with effector to target ratios of 10:1 and 20:1. After 72 h of incubation, surviving tumor cells in 12-well plate were stained by crystal violet and imaged. Relative intensities of surviving cells are shown in the right chart, with IFN-γ-treated sample (10:1 group) set to be 100%. b and c cell killing assays were set up as described above in a 96-well plate. The cytotoxicity of T cells against A375 cells at an effector to target ratio of 10:1 was analyzed using an LDH detection assay kit (percentages calculated as per kit instruction) and remaining cell viability was assessed by MTT assay (control sample set to be 100%). d secreted IL-2 from Jurkat-mediated A375 killing assays was measured using supernatants from cocultures by an IL-2 ELISA kit. Data are represented as mean ± S.D. (n = 3, *P < 0.05 and **P < 0.01)CC BY · PubMed Central
Fig. 6 The influence of apigenin on B16-F10 melanoma xenograft tumor growth and host T cell immunity. a B16-F10 melanoma cells were subcutaneously inoculated into female C57BL/6 wild-type mice. After 4 days, xenograft-bearing mice were randomly divided into 3 groups to receive saline (control), curcumin, or apigenin by daily oral gavage for 12 consecutive days, before sacrifice and tumor resection. b B16-F10 xenograft tumor volume was measured every other day during the treatment and plotted. c the weight of resected B16-F10 xenograft tumor was measured and plotted. d tumor tissue sections were analyzed by immunohistochemistry using anti-Ki-67, anti-CD4, and anti-CD8 antibodies. Scale bar = 50 μm. Magnified insets show CD4 or CD8 positive stained cells. e tumor tissues were lysed to detect PD-L1 expression by immunoblotting. GAPDH was used as a loading control. f splenocyte preparations from different groups were analyzed by flow cytometry with CD4 and CD8 antibodies. g the quantitation of CD4 and CD8 positive cells from different treatment groups in F (total population as 100%). h spleen/body weight ratios of mice with different treatments. i C57BL/6 mice with 3 groups were treated by oral gavage with saline, curcumin (50 mg/kg), or apigenin (150 mg/kg) once a day for 2 weeks. DCs were isolated from mouse spleens and PD-L1 expression in DCs was then detected by immunoblotting. Bar chart shows relative quantification of PD-L1 levels (control as 100%). GAPDH was used as a loading control. Data are presented as mean ± S.D. *P < 0.05, **P < 0.01
Fig. 6 The influence of apigenin on B16-F10 melanoma xenograft tumor growth and host T cell immunity. a B16-F10 melanoma cells were subcutaneously inoculated into female C57BL/6 wild-type mice. After 4 days, xenograft-bearing mice were randomly divided into 3 groups to receive saline (control), curcumin, or apigenin by daily oral gavage for 12 consecutive days, before sacrifice and tumor resection. b B16-F10 xenograft tumor volume was measured every other day during the treatment and plotted. c the weight of resected B16-F10 xenograft tumor was measured and plotted. d tumor tissue sections were analyzed by immunohistochemistry using anti-Ki-67, anti-CD4, and anti-CD8 antibodies. Scale bar = 50 μm. Magnified insets show CD4 or CD8 positive stained cells. e tumor tissues were lysed to detect PD-L1 expression by immunoblotting. GAPDH was used as a loading control. f splenocyte preparations from different groups were analyzed by flow cytometry with CD4 and CD8 antibodies. g the quantitation of CD4 and CD8 positive cells from different treatment groups in F (total population as 100%). h spleen/body weight ratios of mice with different treatments. i C57BL/6 mice with 3 groups were treated by oral gavage with saline, curcumin (50 mg/kg), or apigenin (150 mg/kg) once a day for 2 weeks. DCs were isolated from mouse spleens and PD-L1 expression in DCs was then detected by immunoblotting. Bar chart shows relative quantification of PD-L1 levels (control as 100%). GAPDH was used as a loading control. Data are presented as mean ± S.D. *P < 0.05, **P < 0.01CC BY · PubMed Central
Fig. 7 Apigenin decreases PD-L1 expression in DCs to augment host T cell immunity. a human PBMC-derived DCs were treated with curcumin or apigenin for 24 h and PD-L1 expression was examined by Western blotting. GAPDH was used as a loading control. b quantitation of relative PD-L1 levels from A (control as 100%). c A375 killing assays with CIK and DC-CIK cells. Experimental procedures were described in the methods. d quantitation of the intensity of surviving A375 cells from C (control set as 100%). e cytotoxicity of CIK and DC-CIK cells against A375 as described in C was analyzed using an LDH assay kit. f control, curcumin and apigenin-treated DCs were used in cocultures with CIK cells to generate DC-CIK, DC-CCM-CIK, and DC-APG-CIK, respectively, which were then used in A375 killing assays at an effector to target ratio of 10:1 for 20 h. Surviving A375 cells were stained with crystal violet and imaged. g quantitation data of relative intensities from surviving A375 cells in F (control set as 100%). h cytotoxicity of various DC-CIK cells against A375 was analyzed using an LDH assay kit. Error bars represent S.D. (n = 3, *P < 0.05 and **P < 0.01)
Fig. 7 Apigenin decreases PD-L1 expression in DCs to augment host T cell immunity. a human PBMC-derived DCs were treated with curcumin or apigenin for 24 h and PD-L1 expression was examined by Western blotting. GAPDH was used as a loading control. b quantitation of relative PD-L1 levels from A (control as 100%). c A375 killing assays with CIK and DC-CIK cells. Experimental procedures were described in the methods. d quantitation of the intensity of surviving A375 cells from C (control set as 100%). e cytotoxicity of CIK and DC-CIK cells against A375 as described in C was analyzed using an LDH assay kit. f control, curcumin and apigenin-treated DCs were used in cocultures with CIK cells to generate DC-CIK, DC-CCM-CIK, and DC-APG-CIK, respectively, which were then used in A375 killing assays at an effector to target ratio of 10:1 for 20 h. Surviving A375 cells were stained with crystal violet and imaged. g quantitation data of relative intensities from surviving A375 cells in F (control set as 100%). h cytotoxicity of various DC-CIK cells against A375 was analyzed using an LDH assay kit. Error bars represent S.D. (n = 3, *P < 0.05 and **P < 0.01)CC BY · PubMed Central
Fig. 8 Schematic diagram depicting apigenin and curcumin-mediated inhibition of PD-L1 expression in DCs and melanoma cells. Apigenin and curcumin inhibit IFN-γ-induced STAT1 phosphorylation, leading to reduced PD-L1 expression and surface presentation. Apigenin shows stronger effects than curcumin, with the suppression of PD-L1 expression exerting a dual effect via regulating both tumor and antigen presenting cells (DCs)
Fig. 8 Schematic diagram depicting apigenin and curcumin-mediated inhibition of PD-L1 expression in DCs and melanoma cells. Apigenin and curcumin inhibit IFN-γ-induced STAT1 phosphorylation, leading to reduced PD-L1 expression and surface presentation. Apigenin shows stronger effects than curcumin, with the suppression of PD-L1 expression exerting a dual effect via regulating both tumor and antigen presenting cells (DCs)CC BY · PubMed Central

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Metadata

Authors
Xu, L., Zhang, Y., Tian, K., Chen, X., Zhang, R., Mu, X., Wu, Y., Wang, D., Wang, S., Liu, F., Wang, T., Zhang, J., Liu, S., Zhang, Y., Tu, C., & Liu, H.
Affiliations
Dalian Medical University (CN)
Corresponding author
Liu, Han
ORCID
Venue
Journal of Experimental & Clinical Cancer Research
Publisher
Springer Science and Business Media LLC
Published
2018-10-29
Volume
37
Issue
1
Pages
261-261
ISSN
  • 0392-9078 (ISSN-L)
  • 1756-9966
DOI
10.1186/s13046-018-0929-6
PMC
PMC6206930
OpenAlex
W2898843431
Cited by
177
References
47
Citations by year
2026: 13 · 2025: 21 · 2024: 29 · 2023: 24 · 2022: 26 · 2021: 30 · 2020: 22 · 2019: 12
FWCI
6.01
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Experimental & Clinical Cancer Research (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (81273921, 81601901, 81301901)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Pharmacology (medical) › Flavonoids in Medical Research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
apigenin, melanoma, PD-L1 expression, PD-1/PD-L1 pathway, flavonoids, curcumin, STAT1 phosphorylation, interferon-gamma, apoptosis, T cell cytotoxicity, dendritic cells, cytokine-induced killer cells, tumor xenografts, tumor immune microenvironment, anticancer agents
MeSH terms
Animals, Cell Survival, Curcumin, Dendritic Cells, Humans, Interferon-gamma, Interleukin-2, Melanoma, T-Lymphocytes, Down-Regulation, Gene Expression Regulation, Neoplastic, Coculture Techniques, Jurkat Cells, Xenograft Model Antitumor Assays, Cell Line, Tumor, Apigenin, Cell Proliferation, Mice, B7-H1 Antigen

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