EGCG Inhibits Tumor Growth in Melanoma by Targeting JAK-STAT Signaling and Its Downstream PD-L1/PD-L2-PD1 Axis in Tumors and Enhancing Cytotoxic T-Cell Responses
Over the last decade, therapies targeting immune checkpoints, such as programmed death-1 (PD-1), have revolutionized the field of cancer immunotherapy. However, low response rates and immune-related adverse events remain a major concern. Here, we report that epigallocatechin gallate (EGCG), the most...
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2021
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oai:doaj.org-article:6cf323d74bc0482fa07dc2a10f04c7982021-11-25T18:39:11ZEGCG Inhibits Tumor Growth in Melanoma by Targeting JAK-STAT Signaling and Its Downstream PD-L1/PD-L2-PD1 Axis in Tumors and Enhancing Cytotoxic T-Cell Responses10.3390/ph141110811424-8247https://doaj.org/article/6cf323d74bc0482fa07dc2a10f04c7982021-10-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1081https://doaj.org/toc/1424-8247Over the last decade, therapies targeting immune checkpoints, such as programmed death-1 (PD-1), have revolutionized the field of cancer immunotherapy. However, low response rates and immune-related adverse events remain a major concern. Here, we report that epigallocatechin gallate (EGCG), the most abundant catechin in green tea, inhibits melanoma growth by modulating an immune response against tumors. In vitro experiments revealed that EGCG treatment inhibited interferon-gamma (IFN-γ)-induced PD-L1 and PD-L2 expression and JAK-STAT signaling. We confirmed that this effect was driven by inhibiting <i>STAT1</i> gene expression and STAT1 phosphorylation, thereby downregulating the PD-L1/PD-L2 transcriptional regulator IRF1 in both human and mouse melanoma cells. Animal studies revealed that the in vivo tumor-inhibitory effect of EGCG was through CD8+ T cells and that the inhibitory effect of EGCG was comparable to anti-PD-1 therapy. However, their mechanisms of action were different. Dissimilar to anti-PD-1 treatment that blocks PD-1/PD-L1 interaction, EGCG inhibited JAK/STAT signaling and PD-L1 expression in tumor cells, leading to the re-activation of T cells. In summary, we demonstrate that EGCG enhances anti-tumor immune responses by inhibiting JAK-STAT signaling in melanoma. EGCG could be used as an alternative treatment strategy to target the PD-L1/PD-L2-PD-1 axis in cancers.Dinoop Ravindran MenonYang LiTakeshi YamauchiDouglas Grant OsbornePrasanna Kumar VaddiMichael F WempeZili ZhaiMayumi FujitaMDPI AGarticleEGCGPD-L1PD-L2melanoma immunotherapyIFN-γ signalingJAK-STAT signalingMedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1081, p 1081 (2021) |
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| topic |
EGCG PD-L1 PD-L2 melanoma immunotherapy IFN-γ signaling JAK-STAT signaling Medicine R Pharmacy and materia medica RS1-441 |
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EGCG PD-L1 PD-L2 melanoma immunotherapy IFN-γ signaling JAK-STAT signaling Medicine R Pharmacy and materia medica RS1-441 Dinoop Ravindran Menon Yang Li Takeshi Yamauchi Douglas Grant Osborne Prasanna Kumar Vaddi Michael F Wempe Zili Zhai Mayumi Fujita EGCG Inhibits Tumor Growth in Melanoma by Targeting JAK-STAT Signaling and Its Downstream PD-L1/PD-L2-PD1 Axis in Tumors and Enhancing Cytotoxic T-Cell Responses |
| description |
Over the last decade, therapies targeting immune checkpoints, such as programmed death-1 (PD-1), have revolutionized the field of cancer immunotherapy. However, low response rates and immune-related adverse events remain a major concern. Here, we report that epigallocatechin gallate (EGCG), the most abundant catechin in green tea, inhibits melanoma growth by modulating an immune response against tumors. In vitro experiments revealed that EGCG treatment inhibited interferon-gamma (IFN-γ)-induced PD-L1 and PD-L2 expression and JAK-STAT signaling. We confirmed that this effect was driven by inhibiting <i>STAT1</i> gene expression and STAT1 phosphorylation, thereby downregulating the PD-L1/PD-L2 transcriptional regulator IRF1 in both human and mouse melanoma cells. Animal studies revealed that the in vivo tumor-inhibitory effect of EGCG was through CD8+ T cells and that the inhibitory effect of EGCG was comparable to anti-PD-1 therapy. However, their mechanisms of action were different. Dissimilar to anti-PD-1 treatment that blocks PD-1/PD-L1 interaction, EGCG inhibited JAK/STAT signaling and PD-L1 expression in tumor cells, leading to the re-activation of T cells. In summary, we demonstrate that EGCG enhances anti-tumor immune responses by inhibiting JAK-STAT signaling in melanoma. EGCG could be used as an alternative treatment strategy to target the PD-L1/PD-L2-PD-1 axis in cancers. |
| format |
article |
| author |
Dinoop Ravindran Menon Yang Li Takeshi Yamauchi Douglas Grant Osborne Prasanna Kumar Vaddi Michael F Wempe Zili Zhai Mayumi Fujita |
| author_facet |
Dinoop Ravindran Menon Yang Li Takeshi Yamauchi Douglas Grant Osborne Prasanna Kumar Vaddi Michael F Wempe Zili Zhai Mayumi Fujita |
| author_sort |
Dinoop Ravindran Menon |
| title |
EGCG Inhibits Tumor Growth in Melanoma by Targeting JAK-STAT Signaling and Its Downstream PD-L1/PD-L2-PD1 Axis in Tumors and Enhancing Cytotoxic T-Cell Responses |
| title_short |
EGCG Inhibits Tumor Growth in Melanoma by Targeting JAK-STAT Signaling and Its Downstream PD-L1/PD-L2-PD1 Axis in Tumors and Enhancing Cytotoxic T-Cell Responses |
| title_full |
EGCG Inhibits Tumor Growth in Melanoma by Targeting JAK-STAT Signaling and Its Downstream PD-L1/PD-L2-PD1 Axis in Tumors and Enhancing Cytotoxic T-Cell Responses |
| title_fullStr |
EGCG Inhibits Tumor Growth in Melanoma by Targeting JAK-STAT Signaling and Its Downstream PD-L1/PD-L2-PD1 Axis in Tumors and Enhancing Cytotoxic T-Cell Responses |
| title_full_unstemmed |
EGCG Inhibits Tumor Growth in Melanoma by Targeting JAK-STAT Signaling and Its Downstream PD-L1/PD-L2-PD1 Axis in Tumors and Enhancing Cytotoxic T-Cell Responses |
| title_sort |
egcg inhibits tumor growth in melanoma by targeting jak-stat signaling and its downstream pd-l1/pd-l2-pd1 axis in tumors and enhancing cytotoxic t-cell responses |
| publisher |
MDPI AG |
| publishDate |
2021 |
| url |
https://doaj.org/article/6cf323d74bc0482fa07dc2a10f04c798 |
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