{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T02:56:03Z","timestamp":1791428163465,"version":"4.3.3"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T00:00:00Z","timestamp":1746403200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The CD6\u2010CD318 axis has emerged as a potential target for immuno\u2010oncology. Recent work has shown that blocking the CD6\u2010CD318 interaction with a murine anti\u2010human CD6 antibody increases lymphocyte cytotoxicity. However, several studies have demonstrated the drawbacks associated with the clinical use of murine antibodies and the variability among anti\u2010CD6 antibodies. Therefore, evidence that the first\u2010in\u2010class humanized anti\u2010human CD6 antibody itolizumab could be used for cancer immunotherapy may be a breakthrough in developing an antitumor clinical approach.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Phenotypic and functional characterization of peripheral blood mononuclear cells (PBMCs) from healthy donors after challenge with CD318+ cell lines was performed by flow cytometry. In addition, IFN\u03b3 was determined by ELISA in culture supernatants. Immunohistochemical analyses of breast tumor samples were also performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results and Discussion<\/jats:title><jats:p>Here, we provide evidence supporting the rationale for itolizumab in cancer immunotherapy. The blockade of the CD6-CD318 interaction by itolizumab increases the cytotoxic capacity of CD8 T and NK cells over CD318+ tumor lines, reverses the NKG2A\/NKG2D ratio, and increases granzyme B and IFN\u03b3 production. Itolizumab also regulates immune responses by downregulating CD5 expression and upregulating PD-1 and CTLA-4 inhibitory receptors on lymphocytes, which contribute to reducing exacerbated responses and additively enhancing CD318+ tumor cell cytotoxicity when combined with other immunocheckpoint inhibitors. In addition, we report that CD6\u2010CD318 interaction inhibits lymphocyte proliferation and survival while downregulating CD6 expression on lymphocytes <jats:italic>in vitro<\/jats:italic> and in human breast cancer tissue samples, reinforcing the role of the CD6\u2010CD318 axis as an immune checkpoint and highlighting the potential of itolizumab as an immune checkpoint inhibitor. Taken together, our results provide the first evidence linking the blocking of the CD6-CD318 axis by itolizumab with the potentiation of functional properties of lymphocytes, highlighting itolizumab as a novel promising immunotherapy for CD318+ tumors and supporting the relevance of new combinatorial therapies with checkpoint inhibitors.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1585597","type":"journal-article","created":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T05:10:32Z","timestamp":1746421832000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Itolizumab regulates activating and inhibitory signals on effector cells, improving their cytotoxicity against CD318+ tumor cell lines"],"prefix":"10.3389","volume":"16","author":[{"given":"Cynthia","family":"Gonz\u00e1lez Mu\u00f1oz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rydell","family":"\u00c1lvarez Arzola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adanays","family":"Calvo P\u00e9rez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milagro de la Caridad","family":"Frometa Campan\u00f3n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Hern\u00e1ndez Casa\u00f1a","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aym\u00e9","family":"Fern\u00e1ndez-Calienes Vald\u00e9s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Lorenzo-Luaces","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaima","family":"Mazorra Herrera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"Crombet Ramos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayrel","family":"Labrada Mon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.574271","article-title":"The use of immune checkpoint inhibitors in oncology and the occurrence of AKI: where do we stand","volume":"11","author":"Franzin","year":"2020","journal-title":"Front Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-019-0218-0","article-title":"Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance","volume":"16","author":"Martins","year":"2019","journal-title":"Nat Rev Clin Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2022.1026521","article-title":"The dual role of CD6 as a therapeutic target in cancer and autoimmune disease","volume":"9","author":"Gurrea-Rubio","year":"2022","journal-title":"Front Med (Lausanne)."},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00594","article-title":"Relevance of CD6-mediated interactions in the regulation of peripheral T-cell responses and tolerance","volume":"8","author":"Consuegra-Fernandez","year":"2017","journal-title":"Front Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1159\/000322720","article-title":"The CD6 scavenger receptor is differentially expressed on a CD56 natural killer cell subpopulation and contributes to natural killer-derived cytokine and chemokine secretion","volume":"3","author":"Braun","year":"2011","journal-title":"J Innate Immun"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2010.07.005","article-title":"Aberrant expression of CD6 on B-cell subsets from patients with Sjogren\u2019s syndrome","volume":"35","author":"Alonso","year":"2010","journal-title":"J Autoimmun"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2019.08.008","article-title":"Modulation of CD4 T cell function via CD6-targeting","volume":"47","author":"Freitas","year":"2019","journal-title":"EBioMedicine."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.2174\/1389450116666150531152439","article-title":"Tuning T cell activation: the function of CD6 at the immunological synapse and in T cell responses","volume":"17","author":"Santos","year":"2016","journal-title":"Curr Drug Targets."},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0180088","article-title":"T cell activation and differentiation is modulated by a CD6 domain 1 antibody Itolizumab","volume":"12","author":"Bughani","year":"2017","journal-title":"PloS One"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1615253114","article-title":"CD6 as a potential target for treating multiple sclerosis","volume":"114","author":"Li","year":"2017","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B11","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1002\/eji.201040528","article-title":"CD6 attenuates early and late signaling events, setting thresholds for T-cell activation","volume":"42","author":"Oliveira","year":"2012","journal-title":"Eur J Immunol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1186\/s12964-022-00998-x","article-title":"CD6-mediated inhibition of T cell activation via modulation of Ras","volume":"20","author":"Henriques","year":"2022","journal-title":"Cell Commun Signal"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02994","article-title":"CD6, a rheostat-type signalosome that tunes T cell activation","volume":"9","author":"Goncalves","year":"2018","journal-title":"Front Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20201011","article-title":"The T cell CD6 receptor operates a multitask signalosome with opposite functions in T cell activation","volume":"218","author":"Mori","year":"2021","journal-title":"J Exp Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2015.05.019","article-title":"Structures of CD6 and its ligand CD166 give insight into their interaction","volume":"23","author":"Chappell","year":"2015","journal-title":"Structure."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1704008114","article-title":"CD318 is a ligand for CD6","volume":"114","author":"Enyindah-Asonye","year":"2017","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2014.05.064","article-title":"Modulation of CD6 function through interaction with Galectin-1 and -3","volume":"588","author":"Escoda-Ferran","year":"2014","journal-title":"FEBS Lett"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/jleuko\/qiad124","article-title":"CD6 triggers actomyosin cytoskeleton remodeling after binding to its receptor complex","volume":"115","author":"Borjini","year":"2024","journal-title":"J Leukoc Biol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"17510","DOI":"10.3390\/ijms242417510","article-title":"CD6 and its interacting partners: newcomers to the block of cancer immunotherapies","volume":"24","author":"Aragon-Serrano","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B20","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1186\/s12964-024-01658-y","article-title":"The CD6 interactome orchestrates ligand-independent T cell inhibitory signaling","volume":"22","author":"Santos","year":"2024","journal-title":"Cell Commun Signal"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2019-000172","article-title":"Multifaceted effects of soluble human CD6 in experimental cancer models","volume":"8","author":"Simoes","year":"2020","journal-title":"J Immunother Cancer"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.145662","article-title":"CD6 is a target for cancer immunotherapy","volume":"6","author":"Ruth","year":"2021","journal-title":"JCI Insight"},{"key":"B23","doi-asserted-by":"publisher","first-page":"34.3405677","DOI":"10.21203\/rs.3.rs-3405677\/v1","article-title":"Activation of cytotoxic lymphocytes through CD6 enhances killing of cancer cells","volume":"73","author":"Gurrea-Rubio","year":"2023","journal-title":"Res Sq"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01951","article-title":"The molecular mechanisms that underlie the immune biology of anti-drug antibody formation following treatment with monoclonal antibodies","volume":"11","author":"Vaisman-Mentesh","year":"2020","journal-title":"Front Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.2174\/1389450117666160201114308","article-title":"Therapeutic targeting of CD6 in autoimmune diseases: A review of Cuban clinical studies with the antibodies IOR-T1 and itolizumab","volume":"17","author":"Hernandez","year":"2016","journal-title":"Curr Drug Targets."},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1111\/imm.12952","article-title":"CD6 monoclonal antibodies differ in epitope, kinetics and mechanism of action","volume":"155","author":"Garner","year":"2018","journal-title":"Immunology."},{"key":"B27","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.jaut.2018.02.004","article-title":"Targeting CD6 for the treatment of experimental autoimmune uveitis","volume":"90","author":"Zhang","year":"2018","journal-title":"J Autoimmun"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M209591200","article-title":"The accessory molecules CD5 and CD6 associate on the membrane of lymphoid T cells","volume":"278","author":"Gimferrer","year":"2003","journal-title":"J Biol Chem"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/s41416\u2010023\u201002181\u20106","article-title":"Immune checkpoint inhibitor combinations-current and emerging strategies","volume":"128","author":"Walsh","year":"2023","journal-title":"Br J Cancer."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2021.280444","article-title":"Phenotypic and functional characterization of the CD6-ALCAM T-cell co-stimulatory pathway after allogeneic cell transplantation","volume":"107","author":"Rambaldi","year":"2022","journal-title":"Haematologica."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.22513","article-title":"Human treg cells are characterized by low\/negative CD6 expression","volume":"85","author":"Garcia Santana","year":"2014","journal-title":"Cytometry A."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00769","article-title":"Human CD6 down-modulation following T-cell activation compromises lymphocyte survival and proliferative responses","volume":"8","author":"Carrasco","year":"2017","journal-title":"Front Immunol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"130646","DOI":"10.1155\/2010\/130646","article-title":"Rationale for targeting CD6 as a treatment for autoimmune diseases","volume":"2010","author":"Alonso-Ramirez","year":"2010","journal-title":"Arthritis."},{"key":"B34","doi-asserted-by":"publisher","first-page":"5187","DOI":"10.3390\/cancers13205187","article-title":"The clinical and theranostic values of activated leukocyte cell adhesion molecule (ALCAM)\/CD166 in human solid cancers","volume":"13","author":"Yang","year":"2021","journal-title":"Cancers (Basel)."},{"key":"B35","doi-asserted-by":"publisher","first-page":"101575","DOI":"10.1016\/j.tranon.2022.101575","article-title":"CD166-specific CAR-T cells potently target colorectal cancer cells","volume":"27","author":"He","year":"2023","journal-title":"Transl Oncol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1111\/imm.13009","article-title":"Addition of the C-terminus of CD6 to a chimeric antigen receptor enhances cytotoxicity and does not compromise expression","volume":"156","author":"Breuning","year":"2019","journal-title":"Immunology."},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-20-2978","article-title":"The CDCP1 signaling hub: A target for cancer detection and therapeutic intervention","volume":"81","author":"Khan","year":"2021","journal-title":"Cancer Res"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.03.044","article-title":"Interaction of CDCP1 with HER2 enhances HER2-driven tumorigenesis and promotes trastuzumab resistance in breast cancer","volume":"11","author":"Alajati","year":"2015","journal-title":"Cell Rep"},{"key":"B39","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1038\/s41598-022-26579-z","article-title":"CDCP1 expression is frequently increased in aggressive urothelial carcinoma and promotes urothelial tumor progression","volume":"13","author":"Saponaro","year":"2023","journal-title":"Sci Rep"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2016.7","article-title":"CDCP1 cleavage is necessary for homodimerization-induced migration of triple-negative breast cancer","volume":"35","author":"Wright","year":"2016","journal-title":"Oncogene."},{"key":"B41","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.jpba.2017.02.047","article-title":"Development of an enzyme-linked immunosorbent assay for detection of CDCP1 shed from the cell surface and present in colorectal cancer serum specimens","volume":"139","author":"Chen","year":"2017","journal-title":"J Pharm BioMed Anal"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2012.547","article-title":"In vivo cleaved CDCP1 promotes early tumor dissemination via complexing with activated beta1 integrin and induction of FAK\/PI3K\/Akt motility signaling","volume":"33","author":"Casar","year":"2014","journal-title":"Oncogene."},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1703791114","article-title":"CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation","volume":"114","author":"Wright","year":"2017","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.21037\/tlcr-19-445","article-title":"CD5 and CD6 as immunoregulatory biomarkers in non-small cell lung cancer","volume":"9","author":"Moreno-Manuel","year":"2020","journal-title":"Transl Lung Cancer Res"},{"key":"B45","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1182\/blood-2021-148805","article-title":"Antigenic modulation of CD6 by itolizumab is a new mechanism for effector T cell inhibition","volume":"138","author":"Chu","year":"2021","journal-title":"Blood"},{"key":"B46","doi-asserted-by":"publisher","first-page":"5315","DOI":"10.3390\/ijms22105315","article-title":"Contribution of evolutionary selected immune gene polymorphism to immune-related disorders: the case of lymphocyte scavenger receptors CD5 and CD6","volume":"22","author":"Casado-Llombart","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B47","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1002\/eji.201948309","article-title":"CD5 blockade enhances ex vivo CD8(+) T cell activation and tumour cell cytotoxicity","volume":"50","author":"Alotaibi","year":"2020","journal-title":"Eur J Immunol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.584937","article-title":"Reduced CD5 on CD8(+) T cells in tumors but not lymphoid organs is associated with increased activation and effector function","volume":"11","author":"Alotaibi","year":"2020","journal-title":"Front Immunol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.4161\/onci.22841","article-title":"T-cell modulatory properties of CD5 and its role in antitumor immune responses","volume":"2","author":"Tabbekh","year":"2013","journal-title":"Oncoimmunology."},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1004145","article-title":"Rescue of tumor-infiltrating lymphocytes from activation-induced cell death enhances the antitumor CTL response in CD5-deficient mice","volume":"187","author":"Tabbekh","year":"2011","journal-title":"J Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1585597\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T05:10:34Z","timestamp":1746421834000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1585597\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,5]]},"references-count":50,"alternative-id":["10.3389\/fimmu.2025.1585597"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1585597","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,5]]},"article-number":"1585597"}}