{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:26:28Z","timestamp":1787199988524,"version":"build-2736575974"},"reference-count":35,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["TR004374"],"award-info":[{"award-number":["TR004374"]}]},{"DOI":"10.13039\/100007270","name":"University of Michigan","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007270","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/00jmfr291","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Triple-negative breast cancer (TNBC) is associated with recurrence, metastasis, and limited durable responses to immunotherapy, in part due to persistence of breast cancer stem cells (BCSCs). We investigated whether CD6-directed immunotherapy with the monoclonal antibody UMCD6 enhances immune-mediated killing and alters function of BCSC in stem cell-enriched TNBC models. The SUM-149 and SUM-159 cell lines were analyzed for CD6 ligand expression, cocultured with human peripheral blood mononuclear cells (PBMCs) treated with UMCD6, pembrolizumab, or isotype control, and assessed by live-cell cytotoxicity imaging, flow cytometry, soft agar colony formation, and extreme limiting dilution sphere assays. Both TNBC lines co-expressed the CD6 ligands CD44, CD166\/ALCAM, and CD318\/CDCP1. UMCD6 significantly increased PBMC-mediated apoptosis and reduced tumor cell survival in both models, with greater activity than pembrolizumab under these in vitro conditions. In surviving SUM-159 cells, UMCD6 reduced the ALDH+ population wit\u00d7hout significantly altering CD44+CD24\u2212 frequency, indicating preferential effects on a distinct stem-like compartment. Functionally, UMCD6 decreased anchorage-independent colony formation and reduced sphere-forming frequency from 1\/33.6 to 1\/68.3 cells (p = 0.0186). These findings identify the CD6 ligand axis as a therapeutic vulnerability in BCSC-enriched TNBC and support further preclinical evaluation of CD6-directed immunotherapy as a strategy to enhance antitumor immunity while limiting tumor-initiating capacity.<\/jats:p>","DOI":"10.3390\/biom16081202","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T16:35:08Z","timestamp":1786984508000},"page":"1202","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CD6-Directed Immunotherapy Targets Breast Cancer Stem Cell Function and Enhances Immune-Mediated Cytotoxicity in Triple-Negative Breast Cancer"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0478-1751","authenticated-orcid":false,"given":"Mikel","family":"Gurrea-Rubio","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Sloan","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1175-6721","authenticated-orcid":false,"given":"Aditya","family":"Chada","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila I.","family":"Amarista","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip L.","family":"Campbell","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7149-9115","authenticated-orcid":false,"given":"Pei-Suen","family":"Tsou","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7307-2548","authenticated-orcid":false,"given":"Laura A.","family":"Cooney","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max S.","family":"Wicha","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0230-6607","authenticated-orcid":false,"given":"David A.","family":"Fox","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Freihat, O., Sipos, D., and Kovacs, A. 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