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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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-11-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.724306/full |
| _version_ | 1819034018802302976 |
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| author | Weizhen Li Weizhen Li Yang Zhou Zhongen Wu Yaoping Shi Enming Tian Yingqi Zhu Tao Wang Wei Dou Xiangjing Meng Xiangjing Meng Ming Chen Ming Chen Bo Zhai Bo Zhai Di Zhu Di Zhu |
| author_facet | Weizhen Li Weizhen Li Yang Zhou Zhongen Wu Yaoping Shi Enming Tian Yingqi Zhu Tao Wang Wei Dou Xiangjing Meng Xiangjing Meng Ming Chen Ming Chen Bo Zhai Bo Zhai Di Zhu Di Zhu |
| author_sort | Weizhen Li |
| collection | DOAJ |
| 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-hsBCL9CT-24 displayed synergetic effect against EpCAM-positive colon cells in vitro and also in vivo. A mechanistic study showed that hsBCL9CT-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. |
| first_indexed | 2024-12-21T07:27:04Z |
| format | Article |
| id | doaj.art-e8eaa924bfc24ff78be42a2d416dbc50 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-21T07:27:04Z |
| publishDate | 2021-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-e8eaa924bfc24ff78be42a2d416dbc502022-12-21T19:11:40ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-11-011210.3389/fphar.2021.724306724306Targeting Wnt Signaling in the Tumor Immune Microenvironment to Enhancing EpCAM CAR T-Cell therapyWeizhen Li0Weizhen Li1Yang Zhou2Zhongen Wu3Yaoping Shi4Enming Tian5Yingqi Zhu6Tao Wang7Wei Dou8Xiangjing Meng9Xiangjing Meng10Ming Chen11Ming Chen12Bo Zhai13Bo Zhai14Di Zhu15Di Zhu16Department of Laboratory Medicine, Sixth Affiliated Hospital of Yangzhou University, Taizhou, ChinaDepartment of Laboratory Medicine, Affiliated Taixing Hospital of Bengbu Medical College, Taizhou, ChinaSchool of Pharmacy, Fudan University, Shanghai, ChinaSchool of Pharmacy, Fudan University, Shanghai, ChinaDepartment of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaSchool of Pharmacy, Fudan University, Shanghai, ChinaSchool of Pharmacy, Fudan University, Shanghai, ChinaDepartment of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaShanghai University of Traditional Chinese Medicine, Shanghai, ChinaSchool of Pharmacy, Fudan University, Shanghai, ChinaShandong Academy of Pharmaceutical Science, Jinan, ChinaDepartment of Laboratory Medicine, Sixth Affiliated Hospital of Yangzhou University, Taizhou, ChinaDepartment of Laboratory Medicine, Affiliated Taixing Hospital of Bengbu Medical College, Taizhou, ChinaDepartment of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaState Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaShanghai Engineering Research Center of ImmunoTherapeutics, Fudan University, Shanghai, ChinaDepartment of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, ChinaColorectal 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-hsBCL9CT-24 displayed synergetic effect against EpCAM-positive colon cells in vitro and also in vivo. A mechanistic study showed that hsBCL9CT-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.https://www.frontiersin.org/articles/10.3389/fphar.2021.724306/fullchimeric antigen receptor T cellsWnt signalingBCL9tumor immune microenvironmentEpCAM |
| spellingShingle | Weizhen Li Weizhen Li Yang Zhou Zhongen Wu Yaoping Shi Enming Tian Yingqi Zhu Tao Wang Wei Dou Xiangjing Meng Xiangjing Meng Ming Chen Ming Chen Bo Zhai Bo Zhai Di Zhu Di Zhu Targeting Wnt Signaling in the Tumor Immune Microenvironment to Enhancing EpCAM CAR T-Cell therapy Frontiers in Pharmacology chimeric antigen receptor T cells Wnt signaling BCL9 tumor immune microenvironment EpCAM |
| 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 | chimeric antigen receptor T cells Wnt signaling BCL9 tumor immune microenvironment EpCAM |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2021.724306/full |
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