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β-Catenin induces transcriptional expression of PD-L1 to promote glioblastoma immune evasion

PD-L1 up-regulation in cancer contributes to immune evasion by tumor cells. Here, we show that Wnt ligand and activated EGFR induce the binding of the β-catenin/TCF/LEF complex to the CD274 gene promoter region to induce PD-L1 expression, in which AKT activation plays an important role. β-Catenin de...

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Autores principales: Du, Linyong, Lee, Jong-Ho, Jiang, Hongfei, Wang, Chengde, Wang, Silu, Zheng, Zhihong, Shao, Fei, Xu, Daqian, Xia, Yan, Li, Jing, Zheng, Yanhua, Qian, Xu, Li, Xinjian, Kim, Hyung-Ryong, Xing, Dongming, Liu, Pengyuan, Lu, Zhimin, Lyu, Jianxin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596815/
https://www.ncbi.nlm.nih.gov/pubmed/32860047
http://dx.doi.org/10.1084/jem.20191115
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author Du, Linyong
Lee, Jong-Ho
Jiang, Hongfei
Wang, Chengde
Wang, Silu
Zheng, Zhihong
Shao, Fei
Xu, Daqian
Xia, Yan
Li, Jing
Zheng, Yanhua
Qian, Xu
Li, Xinjian
Kim, Hyung-Ryong
Xing, Dongming
Liu, Pengyuan
Lu, Zhimin
Lyu, Jianxin
author_facet Du, Linyong
Lee, Jong-Ho
Jiang, Hongfei
Wang, Chengde
Wang, Silu
Zheng, Zhihong
Shao, Fei
Xu, Daqian
Xia, Yan
Li, Jing
Zheng, Yanhua
Qian, Xu
Li, Xinjian
Kim, Hyung-Ryong
Xing, Dongming
Liu, Pengyuan
Lu, Zhimin
Lyu, Jianxin
author_sort Du, Linyong
collection PubMed
description PD-L1 up-regulation in cancer contributes to immune evasion by tumor cells. Here, we show that Wnt ligand and activated EGFR induce the binding of the β-catenin/TCF/LEF complex to the CD274 gene promoter region to induce PD-L1 expression, in which AKT activation plays an important role. β-Catenin depletion, AKT inhibition, or PTEN expression reduces PD-L1 expression in tumor cells, enhances activation and tumor infiltration of CD8(+) T cells, and reduces tumor growth, accompanied by prolonged mouse survival. Combined treatment with a clinically available AKT inhibitor and an anti–PD-1 antibody overcomes tumor immune evasion and greatly inhibits tumor growth. In addition, AKT-mediated β-catenin S552 phosphorylation and nuclear β-catenin are positively correlated with PD-L1 expression and inversely correlated with the tumor infiltration of CD8(+) T cells in human glioblastoma specimens, highlighting the clinical significance of β-catenin activation in tumor immune evasion.
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spelling pubmed-75968152021-05-02 β-Catenin induces transcriptional expression of PD-L1 to promote glioblastoma immune evasion Du, Linyong Lee, Jong-Ho Jiang, Hongfei Wang, Chengde Wang, Silu Zheng, Zhihong Shao, Fei Xu, Daqian Xia, Yan Li, Jing Zheng, Yanhua Qian, Xu Li, Xinjian Kim, Hyung-Ryong Xing, Dongming Liu, Pengyuan Lu, Zhimin Lyu, Jianxin J Exp Med Article PD-L1 up-regulation in cancer contributes to immune evasion by tumor cells. Here, we show that Wnt ligand and activated EGFR induce the binding of the β-catenin/TCF/LEF complex to the CD274 gene promoter region to induce PD-L1 expression, in which AKT activation plays an important role. β-Catenin depletion, AKT inhibition, or PTEN expression reduces PD-L1 expression in tumor cells, enhances activation and tumor infiltration of CD8(+) T cells, and reduces tumor growth, accompanied by prolonged mouse survival. Combined treatment with a clinically available AKT inhibitor and an anti–PD-1 antibody overcomes tumor immune evasion and greatly inhibits tumor growth. In addition, AKT-mediated β-catenin S552 phosphorylation and nuclear β-catenin are positively correlated with PD-L1 expression and inversely correlated with the tumor infiltration of CD8(+) T cells in human glioblastoma specimens, highlighting the clinical significance of β-catenin activation in tumor immune evasion. Rockefeller University Press 2020-08-27 /pmc/articles/PMC7596815/ /pubmed/32860047 http://dx.doi.org/10.1084/jem.20191115 Text en This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Du, Linyong
Lee, Jong-Ho
Jiang, Hongfei
Wang, Chengde
Wang, Silu
Zheng, Zhihong
Shao, Fei
Xu, Daqian
Xia, Yan
Li, Jing
Zheng, Yanhua
Qian, Xu
Li, Xinjian
Kim, Hyung-Ryong
Xing, Dongming
Liu, Pengyuan
Lu, Zhimin
Lyu, Jianxin
β-Catenin induces transcriptional expression of PD-L1 to promote glioblastoma immune evasion
title β-Catenin induces transcriptional expression of PD-L1 to promote glioblastoma immune evasion
title_full β-Catenin induces transcriptional expression of PD-L1 to promote glioblastoma immune evasion
title_fullStr β-Catenin induces transcriptional expression of PD-L1 to promote glioblastoma immune evasion
title_full_unstemmed β-Catenin induces transcriptional expression of PD-L1 to promote glioblastoma immune evasion
title_short β-Catenin induces transcriptional expression of PD-L1 to promote glioblastoma immune evasion
title_sort β-catenin induces transcriptional expression of pd-l1 to promote glioblastoma immune evasion
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596815/
https://www.ncbi.nlm.nih.gov/pubmed/32860047
http://dx.doi.org/10.1084/jem.20191115
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