Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen receptor
Chimeric antigen receptor-modulated T lymphocytes (CAR-T) have emerged as a powerful tool for arousing anticancer immunity. Endogenous ligands for tumor antigen may outperform single-chain variable fragments to serve as a component of CARs with high cancer recognition efficacy and minimized immunoge...
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| Veröffentlicht in: | Cancer Immunology, Immunotherapy Immunotherapy, 2018-03, Vol.67 (3), p.393-401 |
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| container_title | Cancer Immunology, Immunotherapy |
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| creator | Zuo, Bai-Le Yan, Bo Zheng, Guo-Xu Xi, Wen-Jin Zhang, Xiao Yang, An-Gang Jia, Lin-Tao |
| description | Chimeric antigen receptor-modulated T lymphocytes (CAR-T) have emerged as a powerful tool for arousing anticancer immunity. Endogenous ligands for tumor antigen may outperform single-chain variable fragments to serve as a component of CARs with high cancer recognition efficacy and minimized immunogenicity. As heterodimerization and signaling partners for human epidermal growth factor receptor 2 (HER2), HER3/HER4 has been implicated in tumorigenic signaling and therapeutic resistance of breast cancer. In this study, we engineered T cells with a CAR consisting of the extracellular domain of heregulin-1β (HRG1β) that is a natural ligand for HER3/HER4, and evaluated the specific cytotoxicity of these CAR-T cells in cultured HER3 positive breast cancer cells and xenograft tumors. Our results showed that HRG1β-CAR was successfully constructed, and T cells were transduced at a rate of 50%. The CAR-T cells specifically recognized and killed HER3-overexpressing breast cancer cells SK-BR-3 and BT-474 in vitro, and displayed potent tumoricidal effect on SK-BR-3 xenograft tumor models. Our results suggest that HRG1β-based CAR-T cells effectively suppress breast cancer driven by HER family receptors, and may provide a novel strategy to overcome cancer resistance to HER2-targeted therapy. |
| doi_str_mv | 10.1007/s00262-017-2089-5 |
| format | Article |
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Endogenous ligands for tumor antigen may outperform single-chain variable fragments to serve as a component of CARs with high cancer recognition efficacy and minimized immunogenicity. As heterodimerization and signaling partners for human epidermal growth factor receptor 2 (HER2), HER3/HER4 has been implicated in tumorigenic signaling and therapeutic resistance of breast cancer. In this study, we engineered T cells with a CAR consisting of the extracellular domain of heregulin-1β (HRG1β) that is a natural ligand for HER3/HER4, and evaluated the specific cytotoxicity of these CAR-T cells in cultured HER3 positive breast cancer cells and xenograft tumors. Our results showed that HRG1β-CAR was successfully constructed, and T cells were transduced at a rate of 50%. The CAR-T cells specifically recognized and killed HER3-overexpressing breast cancer cells SK-BR-3 and BT-474 in vitro, and displayed potent tumoricidal effect on SK-BR-3 xenograft tumor models. Our results suggest that HRG1β-based CAR-T cells effectively suppress breast cancer driven by HER family receptors, and may provide a novel strategy to overcome cancer resistance to HER2-targeted therapy.</description><identifier>ISSN: 0340-7004</identifier><identifier>EISSN: 1432-0851</identifier><identifier>DOI: 10.1007/s00262-017-2089-5</identifier><identifier>PMID: 29127433</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Animals ; Antigens ; Apoptosis ; Breast cancer ; Breast Neoplasms - immunology ; Breast Neoplasms - pathology ; Breast Neoplasms - therapy ; Cancer Research ; Cell Proliferation ; Cell- and Tissue-Based Therapy ; Cells, Cultured ; Chimeric antigen receptors ; Cytotoxicity ; Epidermal growth factor ; ErbB-2 protein ; Female ; Heregulin ; Humans ; Immunogenicity ; Immunology ; Lymphocytes ; Lymphocytes T ; Medicine ; Medicine & Public Health ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neuregulin-1 - metabolism ; Oncology ; Original ; Original Article ; Receptor, ErbB-3 - antagonists & inhibitors ; T-Lymphocytes - immunology ; T-Lymphocytes - transplantation ; T-Lymphocytes, Cytotoxic - immunology ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays ; Xenografts</subject><ispartof>Cancer Immunology, Immunotherapy, 2018-03, Vol.67 (3), p.393-401</ispartof><rights>Springer-Verlag GmbH Germany, part of Springer Nature 2017</rights><rights>Cancer Immunology, Immunotherapy is a copyright of Springer, (2017). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c428t-f258550fcab9011baf332ff768623b373a6ad4943faabe1a573a660146ccf2923</citedby><cites>FETCH-LOGICAL-c428t-f258550fcab9011baf332ff768623b373a6ad4943faabe1a573a660146ccf2923</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11028200/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11028200/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,41464,42533,51294,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29127433$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zuo, Bai-Le</creatorcontrib><creatorcontrib>Yan, Bo</creatorcontrib><creatorcontrib>Zheng, Guo-Xu</creatorcontrib><creatorcontrib>Xi, Wen-Jin</creatorcontrib><creatorcontrib>Zhang, Xiao</creatorcontrib><creatorcontrib>Yang, An-Gang</creatorcontrib><creatorcontrib>Jia, Lin-Tao</creatorcontrib><title>Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen receptor</title><title>Cancer Immunology, Immunotherapy</title><addtitle>Cancer Immunol Immunother</addtitle><addtitle>Cancer Immunol Immunother</addtitle><description>Chimeric antigen receptor-modulated T lymphocytes (CAR-T) have emerged as a powerful tool for arousing anticancer immunity. 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Our results suggest that HRG1β-based CAR-T cells effectively suppress breast cancer driven by HER family receptors, and may provide a novel strategy to overcome cancer resistance to HER2-targeted therapy.</description><subject>Animals</subject><subject>Antigens</subject><subject>Apoptosis</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - immunology</subject><subject>Breast Neoplasms - pathology</subject><subject>Breast Neoplasms - therapy</subject><subject>Cancer Research</subject><subject>Cell Proliferation</subject><subject>Cell- and Tissue-Based Therapy</subject><subject>Cells, Cultured</subject><subject>Chimeric antigen receptors</subject><subject>Cytotoxicity</subject><subject>Epidermal growth factor</subject><subject>ErbB-2 protein</subject><subject>Female</subject><subject>Heregulin</subject><subject>Humans</subject><subject>Immunogenicity</subject><subject>Immunology</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Neuregulin-1 - metabolism</subject><subject>Oncology</subject><subject>Original</subject><subject>Original Article</subject><subject>Receptor, ErbB-3 - antagonists & inhibitors</subject><subject>T-Lymphocytes - immunology</subject><subject>T-Lymphocytes - transplantation</subject><subject>T-Lymphocytes, Cytotoxic - immunology</subject><subject>Tumor Cells, Cultured</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Xenografts</subject><issn>0340-7004</issn><issn>1432-0851</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kU2LFDEQhoMo7rj6A7xIwIuX1krSXzmJLKsrLAgynkM6U-nJ0p20Sfey4683Ta_rB3hKqHrqSYqXkJcM3jKA5l0C4DUvgDUFh1YW1SOyY6XIlbZij8kORAlFA1CekWcp3eQLBymfkjMuGW9KIXbkx17HHmfne6r9gaZlmiKm5IKnwdKry6-imEJys7tF2kXUaaZGe4ORdie6p8NpnI7BnGZMFO-20VVFjxixXwbnqTm6EaMz2T-7Hj2NaHCaQ3xOnlg9JHxxf56Tbx8v9xdXxfWXT58vPlwXpuTtXFhetVUF1uhOAmOdtkJwa5u6rbnoRCN0rQ-lLIXVukOmq7VSAytrYyyXXJyT95t3WroRDwb9HPWgpuhGHU8qaKf-7nh3VH24VYwBbzlANry5N8TwfcE0q9Elg8OgPYYlKSZrwRvO-Iq-_ge9CUv0eT-VTU0jKwl1pthGmRhSimgffsNArdGqLVqVo1VrtKrKM6_-XONh4leWGeAbkHLL9xh_P_1_60_IUrDi</recordid><startdate>20180301</startdate><enddate>20180301</enddate><creator>Zuo, Bai-Le</creator><creator>Yan, Bo</creator><creator>Zheng, Guo-Xu</creator><creator>Xi, Wen-Jin</creator><creator>Zhang, Xiao</creator><creator>Yang, An-Gang</creator><creator>Jia, Lin-Tao</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20180301</creationdate><title>Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen receptor</title><author>Zuo, Bai-Le ; Yan, Bo ; Zheng, Guo-Xu ; Xi, Wen-Jin ; Zhang, Xiao ; Yang, An-Gang ; Jia, Lin-Tao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c428t-f258550fcab9011baf332ff768623b373a6ad4943faabe1a573a660146ccf2923</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Antigens</topic><topic>Apoptosis</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - immunology</topic><topic>Breast Neoplasms - pathology</topic><topic>Breast Neoplasms - therapy</topic><topic>Cancer Research</topic><topic>Cell Proliferation</topic><topic>Cell- and Tissue-Based Therapy</topic><topic>Cells, Cultured</topic><topic>Chimeric antigen receptors</topic><topic>Cytotoxicity</topic><topic>Epidermal growth factor</topic><topic>ErbB-2 protein</topic><topic>Female</topic><topic>Heregulin</topic><topic>Humans</topic><topic>Immunogenicity</topic><topic>Immunology</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Neuregulin-1 - metabolism</topic><topic>Oncology</topic><topic>Original</topic><topic>Original Article</topic><topic>Receptor, ErbB-3 - antagonists & inhibitors</topic><topic>T-Lymphocytes - immunology</topic><topic>T-Lymphocytes - transplantation</topic><topic>T-Lymphocytes, Cytotoxic - immunology</topic><topic>Tumor Cells, Cultured</topic><topic>Xenograft Model Antitumor Assays</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zuo, Bai-Le</creatorcontrib><creatorcontrib>Yan, Bo</creatorcontrib><creatorcontrib>Zheng, Guo-Xu</creatorcontrib><creatorcontrib>Xi, Wen-Jin</creatorcontrib><creatorcontrib>Zhang, Xiao</creatorcontrib><creatorcontrib>Yang, An-Gang</creatorcontrib><creatorcontrib>Jia, Lin-Tao</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Health & Medical Complete (ProQuest Database)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biological Sciences</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer Immunology, Immunotherapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zuo, Bai-Le</au><au>Yan, Bo</au><au>Zheng, Guo-Xu</au><au>Xi, Wen-Jin</au><au>Zhang, Xiao</au><au>Yang, An-Gang</au><au>Jia, Lin-Tao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen receptor</atitle><jtitle>Cancer Immunology, Immunotherapy</jtitle><stitle>Cancer Immunol Immunother</stitle><addtitle>Cancer Immunol Immunother</addtitle><date>2018-03-01</date><risdate>2018</risdate><volume>67</volume><issue>3</issue><spage>393</spage><epage>401</epage><pages>393-401</pages><issn>0340-7004</issn><eissn>1432-0851</eissn><abstract>Chimeric antigen receptor-modulated T lymphocytes (CAR-T) have emerged as a powerful tool for arousing anticancer immunity. Endogenous ligands for tumor antigen may outperform single-chain variable fragments to serve as a component of CARs with high cancer recognition efficacy and minimized immunogenicity. As heterodimerization and signaling partners for human epidermal growth factor receptor 2 (HER2), HER3/HER4 has been implicated in tumorigenic signaling and therapeutic resistance of breast cancer. In this study, we engineered T cells with a CAR consisting of the extracellular domain of heregulin-1β (HRG1β) that is a natural ligand for HER3/HER4, and evaluated the specific cytotoxicity of these CAR-T cells in cultured HER3 positive breast cancer cells and xenograft tumors. Our results showed that HRG1β-CAR was successfully constructed, and T cells were transduced at a rate of 50%. The CAR-T cells specifically recognized and killed HER3-overexpressing breast cancer cells SK-BR-3 and BT-474 in vitro, and displayed potent tumoricidal effect on SK-BR-3 xenograft tumor models. Our results suggest that HRG1β-based CAR-T cells effectively suppress breast cancer driven by HER family receptors, and may provide a novel strategy to overcome cancer resistance to HER2-targeted therapy.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>29127433</pmid><doi>10.1007/s00262-017-2089-5</doi><tpages>9</tpages></addata></record> |
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| subjects | Animals Antigens Apoptosis Breast cancer Breast Neoplasms - immunology Breast Neoplasms - pathology Breast Neoplasms - therapy Cancer Research Cell Proliferation Cell- and Tissue-Based Therapy Cells, Cultured Chimeric antigen receptors Cytotoxicity Epidermal growth factor ErbB-2 protein Female Heregulin Humans Immunogenicity Immunology Lymphocytes Lymphocytes T Medicine Medicine & Public Health Mice Mice, Inbred BALB C Mice, Nude Neuregulin-1 - metabolism Oncology Original Original Article Receptor, ErbB-3 - antagonists & inhibitors T-Lymphocytes - immunology T-Lymphocytes - transplantation T-Lymphocytes, Cytotoxic - immunology Tumor Cells, Cultured Xenograft Model Antitumor Assays Xenografts |
| title | Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen receptor |
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