Metformin Downregulates PD-L1 Expression in Esophageal Squamous Cell Catrcinoma by Inhibiting IL-6 Signaling Pathway

PurposeTo characterize the mechanism by which metformin inhibits PD-L1 expression in esophageal squamous cell carcinoma (ESCC) and to evaluate the effect of metformin on the antitumor immune response.MethodsThe Cancer Genome Atlas (TCGA) database was used to analyze the correlations between IL-6 and...

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Autores principales:	Yao Lu, Dao Xin, Lulu Guan, Mengli Xu, Yalan Yang, Yu Chen, Yuanyuan Yang, Andrea Wang-Gillam, Li Wang, Shanggang Zong, Feng Wang
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	metformin PD-L1 anti-PD-1 antibody esophageal squamous cell carcinoma IL-6/JAK2/STAT3 signaling pathway Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/c861b8c7f13c4c35a4f101a9ac29c246
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spelling	oai:doaj.org-article:c861b8c7f13c4c35a4f101a9ac29c2462021-11-22T05:09:16ZMetformin Downregulates PD-L1 Expression in Esophageal Squamous Cell Catrcinoma by Inhibiting IL-6 Signaling Pathway2234-943X10.3389/fonc.2021.762523https://doaj.org/article/c861b8c7f13c4c35a4f101a9ac29c2462021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.762523/fullhttps://doaj.org/toc/2234-943XPurposeTo characterize the mechanism by which metformin inhibits PD-L1 expression in esophageal squamous cell carcinoma (ESCC) and to evaluate the effect of metformin on the antitumor immune response.MethodsThe Cancer Genome Atlas (TCGA) database was used to analyze the correlations between IL-6 and prognosis and between IL-6 and PD-L1 gene expression in esophageal cancer. Reverse transcription-quantitative polymerase chain reaction (RT-PCR), Western blotting and immunofluorescence were used to study the mechanism by which metformin affects PD-L1 expression. Additionally, T cell function was assessed in a coculture system containing ESCC cells and peripheral blood mononuclear cells (PBMCs) treated with metformin or IL-6. In an in vivo assay, we used a model established with NPIdKO™ mice, which have a reconstituted immune system generated by transplanting PBMCs through intravenous injection, to evaluate the effect of metformin on tumors.ResultsThe TCGA esophageal cancer data showed that IL-6 expression was positively correlated with PD-L1 expression and that patients with high IL-6 expression had a significantly lower overall survival rate than patients with low IL-6 expression. PD-L1 expression in ESCC cell lines was significantly inhibited by metformin via the IL-6/JAK2/STAT3 signaling pathway but was not correlated with the canonical AMPK pathway. In the coculture system, the metformin pretreatment group showed higher T cell activation and better T cell killing function than the control group. Animal experiments confirmed that metformin downregulated PD-L1 expression and that combination treatment with metformin and PD-1 inhibitors synergistically enhanced the antitumor response.ConclusionsMetformin downregulated PD-L1 expression by blocking the IL-6/JAK2/STAT3 signaling pathway in ESCC, which enhanced the antitumor immune response.Yao LuDao XinLulu GuanMengli XuYalan YangYu ChenYuanyuan YangAndrea Wang-GillamLi WangShanggang ZongFeng WangFrontiers Media S.A.articlemetforminPD-L1anti-PD-1 antibodyesophageal squamous cell carcinomaIL-6/JAK2/STAT3 signaling pathwayNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	metformin PD-L1 anti-PD-1 antibody esophageal squamous cell carcinoma IL-6/JAK2/STAT3 signaling pathway Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	metformin PD-L1 anti-PD-1 antibody esophageal squamous cell carcinoma IL-6/JAK2/STAT3 signaling pathway Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Yao Lu Dao Xin Lulu Guan Mengli Xu Yalan Yang Yu Chen Yuanyuan Yang Andrea Wang-Gillam Li Wang Shanggang Zong Feng Wang Metformin Downregulates PD-L1 Expression in Esophageal Squamous Cell Catrcinoma by Inhibiting IL-6 Signaling Pathway
description	PurposeTo characterize the mechanism by which metformin inhibits PD-L1 expression in esophageal squamous cell carcinoma (ESCC) and to evaluate the effect of metformin on the antitumor immune response.MethodsThe Cancer Genome Atlas (TCGA) database was used to analyze the correlations between IL-6 and prognosis and between IL-6 and PD-L1 gene expression in esophageal cancer. Reverse transcription-quantitative polymerase chain reaction (RT-PCR), Western blotting and immunofluorescence were used to study the mechanism by which metformin affects PD-L1 expression. Additionally, T cell function was assessed in a coculture system containing ESCC cells and peripheral blood mononuclear cells (PBMCs) treated with metformin or IL-6. In an in vivo assay, we used a model established with NPIdKO™ mice, which have a reconstituted immune system generated by transplanting PBMCs through intravenous injection, to evaluate the effect of metformin on tumors.ResultsThe TCGA esophageal cancer data showed that IL-6 expression was positively correlated with PD-L1 expression and that patients with high IL-6 expression had a significantly lower overall survival rate than patients with low IL-6 expression. PD-L1 expression in ESCC cell lines was significantly inhibited by metformin via the IL-6/JAK2/STAT3 signaling pathway but was not correlated with the canonical AMPK pathway. In the coculture system, the metformin pretreatment group showed higher T cell activation and better T cell killing function than the control group. Animal experiments confirmed that metformin downregulated PD-L1 expression and that combination treatment with metformin and PD-1 inhibitors synergistically enhanced the antitumor response.ConclusionsMetformin downregulated PD-L1 expression by blocking the IL-6/JAK2/STAT3 signaling pathway in ESCC, which enhanced the antitumor immune response.
format	article
author	Yao Lu Dao Xin Lulu Guan Mengli Xu Yalan Yang Yu Chen Yuanyuan Yang Andrea Wang-Gillam Li Wang Shanggang Zong Feng Wang
author_facet	Yao Lu Dao Xin Lulu Guan Mengli Xu Yalan Yang Yu Chen Yuanyuan Yang Andrea Wang-Gillam Li Wang Shanggang Zong Feng Wang
author_sort	Yao Lu
title	Metformin Downregulates PD-L1 Expression in Esophageal Squamous Cell Catrcinoma by Inhibiting IL-6 Signaling Pathway
title_short	Metformin Downregulates PD-L1 Expression in Esophageal Squamous Cell Catrcinoma by Inhibiting IL-6 Signaling Pathway
title_full	Metformin Downregulates PD-L1 Expression in Esophageal Squamous Cell Catrcinoma by Inhibiting IL-6 Signaling Pathway
title_fullStr	Metformin Downregulates PD-L1 Expression in Esophageal Squamous Cell Catrcinoma by Inhibiting IL-6 Signaling Pathway
title_full_unstemmed	Metformin Downregulates PD-L1 Expression in Esophageal Squamous Cell Catrcinoma by Inhibiting IL-6 Signaling Pathway
title_sort	metformin downregulates pd-l1 expression in esophageal squamous cell catrcinoma by inhibiting il-6 signaling pathway
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/c861b8c7f13c4c35a4f101a9ac29c246
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Metformin Downregulates PD-L1 Expression in Esophageal Squamous Cell Catrcinoma by Inhibiting IL-6 Signaling Pathway

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