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Ephrin receptor A10 monoclonal antibodies and the derived chimeric antigen receptor T cells exert an antitumor response in mouse models of triple-negative breast cancer
Expression of the receptor tyrosine kinase ephrin receptor A10 (EphA10), which is undetectable in most normal tissues except for the male testis, has been shown to correlate with tumor progression and poor prognosis in several malignancies, including triple-negative breast cancer (TNBC). Therefore,...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8988001/ https://www.ncbi.nlm.nih.gov/pubmed/35278434 http://dx.doi.org/10.1016/j.jbc.2022.101817 |
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author | Cha, Jong-Ho Chan, Li-Chuan Wang, Ying-Nai Chu, Yu-Yi Wang, Chie-Hong Lee, Heng-Huan Xia, Weiya Shyu, Woei-Cherng Liu, Shih-Ping Yao, Jun Chang, Chiung-Wen Cheng, Fan-Ru Liu, Jielin Lim, Seung-Oe Hsu, Jennifer L. Yang, Wen-Hao Hortobagyi, Gabriel N. Lin, Chunru Yang, Liuqing Yu, Dihua Jeng, Long-Bin Hung, Mien-Chie |
author_facet | Cha, Jong-Ho Chan, Li-Chuan Wang, Ying-Nai Chu, Yu-Yi Wang, Chie-Hong Lee, Heng-Huan Xia, Weiya Shyu, Woei-Cherng Liu, Shih-Ping Yao, Jun Chang, Chiung-Wen Cheng, Fan-Ru Liu, Jielin Lim, Seung-Oe Hsu, Jennifer L. Yang, Wen-Hao Hortobagyi, Gabriel N. Lin, Chunru Yang, Liuqing Yu, Dihua Jeng, Long-Bin Hung, Mien-Chie |
author_sort | Cha, Jong-Ho |
collection | PubMed |
description | Expression of the receptor tyrosine kinase ephrin receptor A10 (EphA10), which is undetectable in most normal tissues except for the male testis, has been shown to correlate with tumor progression and poor prognosis in several malignancies, including triple-negative breast cancer (TNBC). Therefore, EphA10 could be a potential therapeutic target, likely with minimal adverse effects. However, no effective clinical drugs against EphA10 are currently available. Here, we report high expression levels of EphA10 in tumor regions of breast, lung, and ovarian cancers as well as in immunosuppressive myeloid cells in the tumor microenvironment. Furthermore, we developed anti-EphA10 monoclonal antibodies (mAbs) that specifically recognize cell surface EphA10, but not other EphA family isoforms, and target tumor regions precisely in vivo with no apparent accumulation in other organs. In syngeneic TNBC mouse models, we found that anti-EphA10 mAb clone #4 enhanced tumor regression, therapeutic response rate, and T cell–mediated antitumor immunity. Notably, the chimeric antigen receptor T cells derived from clone #4 significantly inhibited TNBC cell viability in vitro and tumor growth in vivo. Together, our findings suggest that targeting EphA10 via EphA10 mAbs and EphA10-specific chimeric antigen receptor–T cell therapy may represent a promising strategy for patients with EphA10-positive tumors. |
format | Online Article Text |
id | pubmed-8988001 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-89880012022-04-11 Ephrin receptor A10 monoclonal antibodies and the derived chimeric antigen receptor T cells exert an antitumor response in mouse models of triple-negative breast cancer Cha, Jong-Ho Chan, Li-Chuan Wang, Ying-Nai Chu, Yu-Yi Wang, Chie-Hong Lee, Heng-Huan Xia, Weiya Shyu, Woei-Cherng Liu, Shih-Ping Yao, Jun Chang, Chiung-Wen Cheng, Fan-Ru Liu, Jielin Lim, Seung-Oe Hsu, Jennifer L. Yang, Wen-Hao Hortobagyi, Gabriel N. Lin, Chunru Yang, Liuqing Yu, Dihua Jeng, Long-Bin Hung, Mien-Chie J Biol Chem Research Article Expression of the receptor tyrosine kinase ephrin receptor A10 (EphA10), which is undetectable in most normal tissues except for the male testis, has been shown to correlate with tumor progression and poor prognosis in several malignancies, including triple-negative breast cancer (TNBC). Therefore, EphA10 could be a potential therapeutic target, likely with minimal adverse effects. However, no effective clinical drugs against EphA10 are currently available. Here, we report high expression levels of EphA10 in tumor regions of breast, lung, and ovarian cancers as well as in immunosuppressive myeloid cells in the tumor microenvironment. Furthermore, we developed anti-EphA10 monoclonal antibodies (mAbs) that specifically recognize cell surface EphA10, but not other EphA family isoforms, and target tumor regions precisely in vivo with no apparent accumulation in other organs. In syngeneic TNBC mouse models, we found that anti-EphA10 mAb clone #4 enhanced tumor regression, therapeutic response rate, and T cell–mediated antitumor immunity. Notably, the chimeric antigen receptor T cells derived from clone #4 significantly inhibited TNBC cell viability in vitro and tumor growth in vivo. Together, our findings suggest that targeting EphA10 via EphA10 mAbs and EphA10-specific chimeric antigen receptor–T cell therapy may represent a promising strategy for patients with EphA10-positive tumors. American Society for Biochemistry and Molecular Biology 2022-03-10 /pmc/articles/PMC8988001/ /pubmed/35278434 http://dx.doi.org/10.1016/j.jbc.2022.101817 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Article Cha, Jong-Ho Chan, Li-Chuan Wang, Ying-Nai Chu, Yu-Yi Wang, Chie-Hong Lee, Heng-Huan Xia, Weiya Shyu, Woei-Cherng Liu, Shih-Ping Yao, Jun Chang, Chiung-Wen Cheng, Fan-Ru Liu, Jielin Lim, Seung-Oe Hsu, Jennifer L. Yang, Wen-Hao Hortobagyi, Gabriel N. Lin, Chunru Yang, Liuqing Yu, Dihua Jeng, Long-Bin Hung, Mien-Chie Ephrin receptor A10 monoclonal antibodies and the derived chimeric antigen receptor T cells exert an antitumor response in mouse models of triple-negative breast cancer |
title | Ephrin receptor A10 monoclonal antibodies and the derived chimeric antigen receptor T cells exert an antitumor response in mouse models of triple-negative breast cancer |
title_full | Ephrin receptor A10 monoclonal antibodies and the derived chimeric antigen receptor T cells exert an antitumor response in mouse models of triple-negative breast cancer |
title_fullStr | Ephrin receptor A10 monoclonal antibodies and the derived chimeric antigen receptor T cells exert an antitumor response in mouse models of triple-negative breast cancer |
title_full_unstemmed | Ephrin receptor A10 monoclonal antibodies and the derived chimeric antigen receptor T cells exert an antitumor response in mouse models of triple-negative breast cancer |
title_short | Ephrin receptor A10 monoclonal antibodies and the derived chimeric antigen receptor T cells exert an antitumor response in mouse models of triple-negative breast cancer |
title_sort | ephrin receptor a10 monoclonal antibodies and the derived chimeric antigen receptor t cells exert an antitumor response in mouse models of triple-negative breast cancer |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8988001/ https://www.ncbi.nlm.nih.gov/pubmed/35278434 http://dx.doi.org/10.1016/j.jbc.2022.101817 |
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