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Targeting Wnt Signaling in the Tumor Immune Microenvironment to Enhancing EpCAM CAR T-Cell therapy

Colorectal cancer (CRC) patients are still lacking viable treatments. Chimeric antigen receptor (CAR) T cells have shown promise in hematologic malignancies, but their efficacy in solid tumors has been limited due to the immunosuppressive tumor microenvironment. We found that cancer antigen- EpCAM e...

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Autores principales: Li, Weizhen, Zhou, Yang, Wu, Zhongen, Shi, Yaoping, Tian, Enming, Zhu, Yingqi, Wang, Tao, Dou, Wei, Meng, Xiangjing, Chen, Ming, Zhai, Bo, Zhu, Di
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8591126/
https://www.ncbi.nlm.nih.gov/pubmed/34790117
http://dx.doi.org/10.3389/fphar.2021.724306
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author Li, Weizhen
Zhou, Yang
Wu, Zhongen
Shi, Yaoping
Tian, Enming
Zhu, Yingqi
Wang, Tao
Dou, Wei
Meng, Xiangjing
Chen, Ming
Zhai, Bo
Zhu, Di
author_facet Li, Weizhen
Zhou, Yang
Wu, Zhongen
Shi, Yaoping
Tian, Enming
Zhu, Yingqi
Wang, Tao
Dou, Wei
Meng, Xiangjing
Chen, Ming
Zhai, Bo
Zhu, Di
author_sort Li, Weizhen
collection PubMed
description Colorectal cancer (CRC) patients are still lacking viable treatments. Chimeric antigen receptor (CAR) T cells have shown promise in hematologic malignancies, but their efficacy in solid tumors has been limited due to the immunosuppressive tumor microenvironment. We found that cancer antigen- EpCAM expression increased in the metastatic stage compared with the primary stage in cancers and the activation of Wnt and TGFβ pathways was positively correlated with EpCAM expression in multiple cancers, including colorectal cancer. We constructed CAR T cells targeting EpCAM that successfully showed selective cytotoxicity in highly EpCAM-expressing cancer cell lines. The combination of EpCAM CAR-T with the Wnt inhibitor-hsBCL9(CT)-24 displayed synergetic effect against EpCAM-positive colon cells in vitro and also in vivo. A mechanistic study showed that hsBCL9(CT)-24 treatment could modulate the tumor environment and improve infiltration of T cells, while possibly promoting the effector T cells at the early stages and postponing the exhaustion of CAR T cells at advanced stages. Overall, these results demonstrated that the combination of EpCAM CAR T-cell therapy with the Wnt inhibitor can overcome the limitations of CAR T cells in treating solid tumors.
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spelling pubmed-85911262021-11-16 Targeting Wnt Signaling in the Tumor Immune Microenvironment to Enhancing EpCAM CAR T-Cell therapy Li, Weizhen Zhou, Yang Wu, Zhongen Shi, Yaoping Tian, Enming Zhu, Yingqi Wang, Tao Dou, Wei Meng, Xiangjing Chen, Ming Zhai, Bo Zhu, Di Front Pharmacol Pharmacology Colorectal cancer (CRC) patients are still lacking viable treatments. Chimeric antigen receptor (CAR) T cells have shown promise in hematologic malignancies, but their efficacy in solid tumors has been limited due to the immunosuppressive tumor microenvironment. We found that cancer antigen- EpCAM expression increased in the metastatic stage compared with the primary stage in cancers and the activation of Wnt and TGFβ pathways was positively correlated with EpCAM expression in multiple cancers, including colorectal cancer. We constructed CAR T cells targeting EpCAM that successfully showed selective cytotoxicity in highly EpCAM-expressing cancer cell lines. The combination of EpCAM CAR-T with the Wnt inhibitor-hsBCL9(CT)-24 displayed synergetic effect against EpCAM-positive colon cells in vitro and also in vivo. A mechanistic study showed that hsBCL9(CT)-24 treatment could modulate the tumor environment and improve infiltration of T cells, while possibly promoting the effector T cells at the early stages and postponing the exhaustion of CAR T cells at advanced stages. Overall, these results demonstrated that the combination of EpCAM CAR T-cell therapy with the Wnt inhibitor can overcome the limitations of CAR T cells in treating solid tumors. Frontiers Media S.A. 2021-11-01 /pmc/articles/PMC8591126/ /pubmed/34790117 http://dx.doi.org/10.3389/fphar.2021.724306 Text en Copyright © 2021 Li, Zhou, Wu, Shi, Tian, Zhu, Wang, Dou, Meng, Chen, Zhai and Zhu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Li, Weizhen
Zhou, Yang
Wu, Zhongen
Shi, Yaoping
Tian, Enming
Zhu, Yingqi
Wang, Tao
Dou, Wei
Meng, Xiangjing
Chen, Ming
Zhai, Bo
Zhu, Di
Targeting Wnt Signaling in the Tumor Immune Microenvironment to Enhancing EpCAM CAR T-Cell therapy
title Targeting Wnt Signaling in the Tumor Immune Microenvironment to Enhancing EpCAM CAR T-Cell therapy
title_full Targeting Wnt Signaling in the Tumor Immune Microenvironment to Enhancing EpCAM CAR T-Cell therapy
title_fullStr Targeting Wnt Signaling in the Tumor Immune Microenvironment to Enhancing EpCAM CAR T-Cell therapy
title_full_unstemmed Targeting Wnt Signaling in the Tumor Immune Microenvironment to Enhancing EpCAM CAR T-Cell therapy
title_short Targeting Wnt Signaling in the Tumor Immune Microenvironment to Enhancing EpCAM CAR T-Cell therapy
title_sort targeting wnt signaling in the tumor immune microenvironment to enhancing epcam car t-cell therapy
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8591126/
https://www.ncbi.nlm.nih.gov/pubmed/34790117
http://dx.doi.org/10.3389/fphar.2021.724306
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