{"doi":"10.1016/j.jbc.2022.101817","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","abstract":"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. 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. Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) expression. Prognosis in patients with advanced TNBC remains poor, in part due to the limited number of effective therapeutic options. In addition, the high risk of recurrence and resistance to chemotherapy in TNBC remains a substantial clinical challenge. Thus, a novel therapeutic strategy for patients with TNBC is considered an unmet medical need (1Harbeck N. Penault-Llorca F. Cortes J. Gnant M. Houssami N. Poortmans P. Ruddy K. Tsang J. Cardoso F. Breast cancer.Nat. Rev. Dis. primers. 2019; 5: 66Crossref PubMed Scopus (729) Google Scholar, 2Carey L.A. Finding the positive in triple-negative breast cancer.Nat. Cancer. 2021; 2: 476-478Crossref PubMed Scopus (1) Google Scholar). Preclinical and clinical data suggest that antitumor immunity is a critical determinant of outcome in TNBC. Specifically, higher quantities of tumor-infiltrating cytotoxic T lymphocytes (CTLs) have been associated with response to chemotherapy and improved survival in TNBC, suggesting that modulating the t","journal":"Journal of Biological Chemistry","year":2022,"id":254202,"datarank":0.8149464884342399,"base_score":3.091042453358316,"endowment":3.091042453358316,"self_citation_contribution":0.4636563680037475,"citation_network_contribution":0.3512901204304924,"self_endowment_contribution":0.4636563680037475,"citer_contribution":0.3512901204304924,"corpus_percentile":null,"corpus_rank":null,"citation_count":21,"citer_count":19,"citers_with_citation_signal":18,"citers_with_endowment":18,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":251994,"name":"Li-Chuan Chan","orcid":"0000-0002-2665-637X","position":1,"is_corresponding":false},{"id":247181,"name":"Ying‐Nai Wang","orcid":"0000-0002-5275-6729","position":2,"is_corresponding":false},{"id":866504,"name":"Yu‐Yi Chu","orcid":"0000-0003-3780-3061","position":3,"is_corresponding":false},{"id":900764,"name":"Chie‐Hong Wang","orcid":"0000-0003-0774-5323","position":4,"is_corresponding":false},{"id":247182,"name":"Heng‐Huan Lee","orcid":"0000-0002-7813-1292","position":5,"is_corresponding":false},{"id":107243,"name":"Weiya Xia","orcid":null,"position":6,"is_corresponding":false},{"id":900765,"name":"Woei‐Cherng Shyu","orcid":"0000-0002-3335-8450","position":7,"is_corresponding":false},{"id":900766,"name":"Shih‐Ping Liu","orcid":"0000-0002-5803-4460","position":8,"is_corresponding":false},{"id":251992,"name":"Jun Yao","orcid":"0000-0003-1418-3576","position":9,"is_corresponding":false},{"id":107244,"name":"Chiung-Wen Chang","orcid":null,"position":10,"is_corresponding":false},{"id":901347,"name":"Fan-Ru Cheng","orcid":null,"position":11,"is_corresponding":false},{"id":251989,"name":"Jielin Liu","orcid":"0000-0001-9596-8943","position":12,"is_corresponding":false},{"id":477599,"name":"Seung‐Oe Lim","orcid":"0000-0002-8138-4549","position":13,"is_corresponding":false},{"id":107254,"name":"Jennifer L. Hsu","orcid":"0000-0001-9920-0720","position":14,"is_corresponding":false},{"id":696219,"name":"Wenhao Yang","orcid":"0000-0002-6292-9048","position":15,"is_corresponding":false},{"id":299476,"name":"Gabriel N. Hortobágyi","orcid":"0000-0002-4873-4412","position":16,"is_corresponding":false},{"id":288693,"name":"Chunru Lin","orcid":"0000-0002-6473-8229","position":17,"is_corresponding":false},{"id":288694,"name":"Liuqing Yang","orcid":"0000-0002-6518-474X","position":18,"is_corresponding":false},{"id":105030,"name":"Dihua Yu","orcid":"0000-0001-6231-9381","position":19,"is_corresponding":false},{"id":900767,"name":"Long‐Bin Jeng","orcid":"0000-0002-2928-4698","position":20,"is_corresponding":false},{"id":107263,"name":"Mien‐Chie Hung","orcid":"0000-0003-4317-4740","position":21,"is_corresponding":false},{"id":251993,"name":"Jong‐Ho Cha","orcid":"0000-0003-2181-7768","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:25:03.918844Z","pmid":"35278434","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}