TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors
In recent years, chimeric antigen receptor-modified T cell (CAR T cell) therapy has proven to be a promising approach against cancer. Nonetheless, this approach still faces multiple challenges in eliminating solid tumors, one of which being the immunosuppressive tumor microenvironment (TME). Here, w...
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| Published in: | JCI insight Vol. 5; no. 4 |
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| Main Authors: | , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
American Society for Clinical Investigation
27.02.2020
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| Subjects: | |
| ISSN: | 2379-3708, 2379-3708 |
| Online Access: | Get full text |
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| Abstract | In recent years, chimeric antigen receptor-modified T cell (CAR T cell) therapy has proven to be a promising approach against cancer. Nonetheless, this approach still faces multiple challenges in eliminating solid tumors, one of which being the immunosuppressive tumor microenvironment (TME). Here, we demonstrated that knocking out the endogenous TGF-β receptor II (TGFBR2) in CAR T cells with CRISPR/Cas9 technology could reduce the induced Treg conversion and prevent the exhaustion of CAR T ce lls. Meanwhile, TGFBR2-edited CAR T cells had better in vivo tumor elimination efficacy, both in cell line-derived xenograft and patient-derived xenograft solid tumor models, whether administered locally or systemically. In addition, the TGFBR2-edited CAR T cells could eliminate contralaterally reinoculated xenografts in mice effectively, with an increased proportion of memory subsets within circulating CAR T cells of central memory and effector memory subsets. In conclusion, we greatly improved the in vitro and in vivo function of CAR T cells in TGF-β-rich tumor environments by knocking out endogenous TGFBR2 and propose a potentially new method to improve the efficacy of CAR T cell therapy for treating solid tumors. |
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| AbstractList | In recent years, chimeric antigen receptor-modified T cell (CAR T cell) therapy has proven to be a promising approach against cancer. Nonetheless, this approach still faces multiple challenges in eliminating solid tumors, one of which being the immunosuppressive tumor microenvironment (TME). Here, we demonstrated that knocking out the endogenous TGF-β receptor II (TGFBR2) in CAR T cells with CRISPR/Cas9 technology could reduce the induced Treg conversion and prevent the exhaustion of CAR T ce lls. Meanwhile, TGFBR2-edited CAR T cells had better in vivo tumor elimination efficacy, both in cell line-derived xenograft and patient-derived xenograft solid tumor models, whether administered locally or systemically. In addition, the TGFBR2-edited CAR T cells could eliminate contralaterally reinoculated xenografts in mice effectively, with an increased proportion of memory subsets within circulating CAR T cells of central memory and effector memory subsets. In conclusion, we greatly improved the in vitro and in vivo function of CAR T cells in TGF-β-rich tumor environments by knocking out endogenous TGFBR2 and propose a potentially new method to improve the efficacy of CAR T cell therapy for treating solid tumors. In recent years, chimeric antigen receptor-modified T cell (CAR T cell) therapy has proven to be a promising approach against cancer. Nonetheless, this approach still faces multiple challenges in eliminating solid tumors, one of which being the immunosuppressive tumor microenvironment (TME). Here, we demonstrated that knocking out the endogenous TGF-β receptor II (TGFBR2) in CAR T cells with CRISPR/Cas9 technology could reduce the induced Treg conversion and prevent the exhaustion of CAR T ce lls. Meanwhile, TGFBR2-edited CAR T cells had better in vivo tumor elimination efficacy, both in cell line-derived xenograft and patient-derived xenograft solid tumor models, whether administered locally or systemically. In addition, the TGFBR2-edited CAR T cells could eliminate contralaterally reinoculated xenografts in mice effectively, with an increased proportion of memory subsets within circulating CAR T cells of central memory and effector memory subsets. In conclusion, we greatly improved the in vitro and in vivo function of CAR T cells in TGF-β-rich tumor environments by knocking out endogenous TGFBR2 and propose a potentially new method to improve the efficacy of CAR T cell therapy for treating solid tumors.In recent years, chimeric antigen receptor-modified T cell (CAR T cell) therapy has proven to be a promising approach against cancer. Nonetheless, this approach still faces multiple challenges in eliminating solid tumors, one of which being the immunosuppressive tumor microenvironment (TME). Here, we demonstrated that knocking out the endogenous TGF-β receptor II (TGFBR2) in CAR T cells with CRISPR/Cas9 technology could reduce the induced Treg conversion and prevent the exhaustion of CAR T ce lls. Meanwhile, TGFBR2-edited CAR T cells had better in vivo tumor elimination efficacy, both in cell line-derived xenograft and patient-derived xenograft solid tumor models, whether administered locally or systemically. In addition, the TGFBR2-edited CAR T cells could eliminate contralaterally reinoculated xenografts in mice effectively, with an increased proportion of memory subsets within circulating CAR T cells of central memory and effector memory subsets. In conclusion, we greatly improved the in vitro and in vivo function of CAR T cells in TGF-β-rich tumor environments by knocking out endogenous TGFBR2 and propose a potentially new method to improve the efficacy of CAR T cell therapy for treating solid tumors. In recent years, chimeric antigen receptor–modified T cell (CAR T cell) therapy has proven to be a promising approach against cancer. Nonetheless, this approach still faces multiple challenges in eliminating solid tumors, one of which being the immunosuppressive tumor microenvironment (TME). Here, we demonstrated that knocking out the endogenous TGF-β receptor II (TGFBR2) in CAR T cells with CRISPR/Cas9 technology could reduce the induced Treg conversion and prevent the exhaustion of CAR T ce lls. Meanwhile, TGFBR2-edited CAR T cells had better in vivo tumor elimination efficacy, both in cell line–derived xenograft and patient-derived xenograft solid tumor models, whether administered locally or systemically. In addition, the TGFBR2-edited CAR T cells could eliminate contralaterally reinoculated xenografts in mice effectively, with an increased proportion of memory subsets within circulating CAR T cells of central memory and effector memory subsets. In conclusion, we greatly improved the in vitro and in vivo function of CAR T cells in TGF-β–rich tumor environments by knocking out endogenous TGFBR2 and propose a potentially new method to improve the efficacy of CAR T cell therapy for treating solid tumors. Inhibition of the immunosuppressive TGFβ signaling by knocking out endogenous TGFBR2 greatly improved the persistence and efficacy of CAR-T cells against solid tumors in mice. |
| Author | Cheng, Chen Wang, Haoyi Qiao, Miaomiao Zhang, Xingying Han, Weidong Li, Na Tang, Na Mu, Wei Wei, Xiao-Fei |
| AuthorAffiliation | 4 Beijing Cord Blood Bank, Beijing, China 6 Department of Molecular Biology and Immunology, Chinese People’s Liberation Army General Hospital, Beijing, China 5 Biotherapeutic Department and 1 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China 3 University of Chinese Academy of Sciences, Beijing, China 2 School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China 7 Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China |
| AuthorAffiliation_xml | – name: 6 Department of Molecular Biology and Immunology, Chinese People’s Liberation Army General Hospital, Beijing, China – name: 4 Beijing Cord Blood Bank, Beijing, China – name: 2 School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China – name: 5 Biotherapeutic Department and – name: 7 Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China – name: 1 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China – name: 3 University of Chinese Academy of Sciences, Beijing, China |
| Author_xml | – sequence: 1 givenname: Na surname: Tang fullname: Tang, Na – sequence: 2 givenname: Chen surname: Cheng fullname: Cheng, Chen – sequence: 3 givenname: Xingying surname: Zhang fullname: Zhang, Xingying – sequence: 4 givenname: Miaomiao surname: Qiao fullname: Qiao, Miaomiao – sequence: 5 givenname: Na surname: Li fullname: Li, Na – sequence: 6 givenname: Wei surname: Mu fullname: Mu, Wei – sequence: 7 givenname: Xiao-Fei orcidid: 0000-0001-6775-346X surname: Wei fullname: Wei, Xiao-Fei – sequence: 8 givenname: Weidong surname: Han fullname: Han, Weidong – sequence: 9 givenname: Haoyi surname: Wang fullname: Wang, Haoyi |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/31999649$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | 2020. This work is published under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 2020 American Society for Clinical Investigation 2020 American Society for Clinical Investigation |
| Copyright_xml | – notice: 2020. This work is published under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. – notice: 2020 American Society for Clinical Investigation 2020 American Society for Clinical Investigation |
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| SubjectTerms | Antigens Cancer Cell therapy Chimeric antigen receptors CRISPR Cytokines Cytotoxicity Genes Immunological memory Ligands Lymphocytes Lymphocytes T Memory cells Solid tumors Transforming growth factor-b Tumor microenvironment Tumors Xenografts |
| Title | TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors |
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