{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T22:43:16Z","timestamp":1769726596317,"version":"3.49.0"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T00:00:00Z","timestamp":1734048000000},"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>T cell Antigen Coupler (TAC) T cells harness all signaling subunits of endogenous T cell receptor (TCR) to trigger T-cell activation and tumor cell lysis, with minimal release of cytokines. Some of the major obstacles to cellular immunotherapy in solid tumors include inefficient cell infiltration into tumors, lack of prolonged cellular persistence, and therapy-associated toxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To boost the cytotoxic potential of TAC-T cells against solid tumors, we generated a novel NECTIN-4-targeted TAC-T variant, NECTIN-4 TAC28-T, which integrated the co-stimulatory CD28 cytoplasmic region, and compared the anti-tumor activities between NECTIN-4 TAC-T cells and NECTIN-4 TAC28-T cells in vitro and vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We demonstrated NECTIN-4 TAC28-Tcells could be effectively activated by NECTIN-4 protein-coated magnetic beads (NECTIN-4-beads), and further revealed that the incorporated CD28 co-stimulatory domain enhanced their activation and proliferation capabilities. Notably, NECTIN-4 TAC28-T cells exhibited better anti-tumor effects both in vitro and in vivo than the original NECTIN-4 TAC-T cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our data highlighted  that NECTIN-4 TAC28-T cells may represent a promising, safe and effective cell therapy for NECTIN-4-overexpressing solid tumors.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1456443","type":"journal-article","created":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T06:22:06Z","timestamp":1734070926000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["NECTIN-4-redirected T cell Antigen Coupler T cells bearing CD28 show superior antitumor responses against solid tumors"],"prefix":"10.3389","volume":"15","author":[{"given":"Cheng","family":"Wei","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianlong","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yinan","family":"Fang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiaolin","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peiyuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qianjin","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Binjiao","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongping","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qichuan","family":"Zhuge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ai","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jimin","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinhong","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,12,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s00428-018-2484-0","article-title":"Adoptive cellular therapies: the current landscape","volume":"474","author":"Rohaan, Maartje","year":"2019","journal-title":"Virchows Archiv"},{"key":"B2","doi-asserted-by":"publisher","first-page":"410","DOI":"10.3390\/cells11030410","article-title":"Adoptive cellular therapy for multiple myeloma using CAR-and TCR-transgenic T cells: Response and resistance","author":"F\u00fcchsl","year":"2022","journal-title":"Cells"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-02017-5","article-title":"Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus","author":"Mackensen","year":"2022","journal-title":"Nat Med"},{"key":"B4","doi-asserted-by":"publisher","first-page":"101459","DOI":"10.1016\/j.tranon.2022.101459","article-title":"Resistance against anti-CD19 and anti-BCMA CAR T cells: Recent advances and coping strategies","volume":"22","author":"Pinar Ataca","year":"2022","journal-title":"Trans Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41409-020-01134-4","article-title":"Taming the beast: CRS and ICANS after CAR T-cell therapy for ALL","volume":"56","author":"Sheth","year":"2021","journal-title":"Bone Marrow Transplant"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-003847","article-title":"Single-center experience using anakinra for steroid-refractory immune effector cell-associated neurotoxicity syndrome (ICANS)","volume":"10","author":"Wehrli","year":"2022","journal-title":"J Immunother Cancer"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.663201","article-title":"Reactions related to CAR-T cell therapy","volume":"12","author":"Miao","year":"2021","journal-title":"Front Immunol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"3049","DOI":"10.1038\/s41467-018-05395-y","article-title":"The chimeric TAC receptor co-opts the T cell receptor yielding robust anti-tumor activity without toxicity","volume":"9","author":"Helsen","year":"2018","journal-title":"Nat Commun"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2020-141925","article-title":"Tonic signaling leads to off-target activation of T cells engineered with chimeric antigen receptors that is not seen in T cells engineered with T cell antigen coupler (TAC) receptors","volume":"136","author":"Moogk","year":"2020","journal-title":"Blood"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-014-1763-4","article-title":"Nectin family of cell-adhesion molecules: structural and molecular aspects of function and specificity","volume":"72","author":"Dibyendu","year":"2015","journal-title":"Cell Mol Life Sci"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-0016","article-title":"Identification of Nectin-4 oncoprotein as a diagnostic and therapeutic target for lung cancer","author":"Atsushi","year":"2009","journal-title":"Cancer Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1309\/AJCPGXK0FR4MHIHB","article-title":"Nectin 4 overexpression in ovarian cancer tissues and serum: potential role as a serum biomarker","author":"DeRycke","year":"2010","journal-title":"Am J Clin Pathol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13046-015-0144-7","article-title":"Nectin-4 expression contributes to tumor proliferation, angiogenesis and patient prognosis in human pancreatic cancer","author":"Nishiwada","year":"2015","journal-title":"J Exp Clin Cancer Res"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/oncolo\/oyac001","article-title":"Management of dermatologic events associated with the Nectin-4-directed antibody-drug conjugate enfortumab vedotin","author":"Lacouture","year":"2022","journal-title":"oncologist"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1080\/14712598.2021.1929168","article-title":"Targeting nectin-4 by antibody-drug conjugates for the treatment of urothelial carcinoma","author":"Wong","year":"2021","journal-title":"Expert Opin Biol Ther"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.958082","article-title":"Development of Nectin4\/FAP-targeted CAR-T cells secreting IL-7, CCL19, and IL-12 for Malignant solid tumors","author":"Li","year":"2022","journal-title":"Front Immunol 13"},{"key":"B17","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/s12943-023-01723-z","article-title":"CAR-cell therapy in the era of solid tumor treatment: current challenges and emerging therapeutic advances","volume":"22","author":"Maalej","year":"2023","journal-title":"Mol Cancer"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.04.020","article-title":"CD28 costimulation: from mechanism to therapy","volume":"44","author":"Esensten","year":"2016","journal-title":"Immunity"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.2147\/ITT.S61647","article-title":"CD28 co-stimulation in T-cell homeostasis: a recent perspective","volume":"4","author":"Beyersdorf","year":"2015","journal-title":"Immunotargets Ther"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/nri3405","article-title":"Molecular mechanisms of T cell co-stimulation and co-inhibition","volume":"13","author":"Chen","year":"2013","journal-title":"Nat Rev Immunol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/978-981-32-9717-3","article-title":"Co-signal molecules in T-cell activation: historical overview and perspective","volume":"1189","author":"Azuma","year":"2019","journal-title":"Adv Exp Med Biol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-022-04493-1","article-title":"HLA and tumour immunology: immune escape, immunotherapy and immune-related adverse events","volume":"149","author":"Jiang","year":"2023","journal-title":"J Cancer Res Clin Oncol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines5010007","article-title":"The escape of cancer from T cell-mediated immune surveillance: HLA class I loss and tumor tissue architecture","volume":"5","author":"Garrido","year":"2017","journal-title":"Vaccines (Basel)"},{"key":"B24","article-title":"Immunomodulatory molecules in renal cell cancer: CD80 and CD86 are expressed on tumor cells","volume":"10","author":"Fl\u00f6rcken","year":"2017","journal-title":"Int J Clin Exp Pathol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1084\/jem.181.5.1653","article-title":"Signals through T cell receptor-zeta chain alone are insufficient to prime resting T lymphocytes","volume":"181","author":"Brocker","year":"1995","journal-title":"J Exp Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-12-128843","article-title":"Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells","volume":"112","author":"Till","year":"2008","journal-title":"Blood"},{"key":"B27","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1172\/JCI46110","article-title":"CD28 costimulation improves expansion and persistence of chimeric antigen receptor\u2013modified T cells in lymphoma patients","volume":"121","author":"Savoldo","year":"2011","journal-title":"J Clin Invest"},{"key":"B28","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1038\/nrd4597","article-title":"The pharmacology of second-generation chimeric antigen receptors","volume":"14","author":"van der Stegen","year":"2015","journal-title":"Nat Rev Drug Discovery"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdw678","article-title":"Nectin-4: a new prognostic biomarker for efficient therapeutic targeting of primary and metastatic triple-negative breast cancer","volume":"28","author":"MR","year":"2017","journal-title":"Ann Oncol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1084\/jem.175.1.217","article-title":"Development of humanized bispecific antibodies reactive with cytotoxic lymphocytes and tumor cells overexpressing the HER2 protooncogene","volume":"175","author":"Shalaby","year":"1992","journal-title":"J Exp Med"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.155.4.1903","article-title":"Identification of heavy chain residues in a humanized anti-CD3 antibody important for efficient antigen binding and T cell activation","volume":"155","author":"Zhu","year":"1995","journal-title":"J Immunol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.xcrm.2023.100917","article-title":"CD28-CAR-T cell activation through FYN kinase signaling rather than LCK enhances therapeutic performance","volume":"4","author":"Wu","year":"2023","journal-title":"Cell Rep Med"},{"key":"B33","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1158\/2326-6066.CIR-20-0253","article-title":"CD28 costimulatory domain\u2013targeted mutations enhance chimeric antigen receptor T-cell function","author":"Boucher","year":"2021","journal-title":"Cancer Immunol Res"},{"key":"B34","doi-asserted-by":"publisher","first-page":"100826","DOI":"10.1016\/j.currproblcancer.2021.100826","article-title":"CAR T-cell therapy for B-cell lymphoma","author":"Denlinger","year":"2022","journal-title":"Curr problems Cancer"},{"key":"B35","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1038\/d41573-022-00048-8","article-title":"FDA approves second BCMA-targeted CAR-T cell therapy","author":"Mullard","year":"2022","journal-title":"Nat Rev Drug Discov"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26844-1","article-title":"Transient mTOR inhibition rescues 4-1BB CAR-Tregs from tonic signal-induced dysfunction","author":"Lamarth\u00e9e","year":"2021","journal-title":"Nat Commun"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2020-141925","article-title":"Tonic signaling leads to off-target activation of T cells engineered with chimeric antigen receptors that is not seen in T cells engineered with T cell antigen coupler (TAC) receptors","volume":"136","author":"Moogk","year":"2020","journal-title":"Blood"},{"key":"B38","doi-asserted-by":"publisher","first-page":"36","DOI":"10.3390\/cancers8030036","article-title":"Different subsets of T cells, memory, effector functions, and CAR-T immunotherapy","author":"Golubovskaya","year":"2016","journal-title":"Cancers"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1081\/imm-120030732","article-title":"The interleukin (IL)-2 family cytokines: survival and proliferation signaling pathways in T lymphocytes","author":"Benczik","year":"2004","journal-title":"Immunol investigations"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0398-2","article-title":"Interleukin-23 engineering improves CAR T cell function in solid tumors","author":"Ma","year":"2020","journal-title":"Nat Biotechnol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0002404","article-title":"An IFN-\u03b3-IL-18 signaling loop accelerates memory CD8+ T cell proliferation","author":"Iwai","year":"2008","journal-title":"PloS One"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.04.005","article-title":"Metabolic pathways in immune cell activation and quiescence","volume":"38","author":"Pearce","year":"2013","journal-title":"Immunity"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2386","article-title":"Metabolic checkpoints in activated T cells","volume":"13","author":"Wang","year":"2012","journal-title":"Nat Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/nature08097","article-title":"Enhancing CD8 T-cell memory by modulating fatty acid metabolism","volume":"460","author":"Pearce","year":"2009","journal-title":"Nature"},{"key":"B45","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.immuni.2011.12.007","article-title":"Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development","volume":"36","author":"van der Windt","year":"2012","journal-title":"Immunity"},{"key":"B46","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.trsl.2018.07.013","article-title":"Targeting mitochondria in cancer: current concepts and immunotherapy approaches","volume":"202","author":"Pustylnikov","year":"2018","journal-title":"Trans Res"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2015.09.004","article-title":"Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells","volume":"28","author":"Zhao","year":"2015","journal-title":"Cancer Cell"},{"key":"B48","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1016\/j.ccell.2019.12.014","article-title":"THEMIS-SHP1 recruitment by 4-1BB tunes LCK-mediated priming of chimeric antigen receptor-redirected T cells","volume":"37","author":"Sun","year":"2020","journal-title":"Cancer Cell"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aat6753","article-title":"Phosphoproteomic analysis of chimeric antigen receptor signaling reveals kinetic and quantitative differences that affect cell function","volume":"11","author":"Salter","year":"2018","journal-title":"Sci Signal"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.01.028","article-title":"The proteomic landscape of human ex vivo regulatory and conventional T cells reveals specific metabolic requirements","volume":"44","author":"Procaccini","year":"2016","journal-title":"Immunity"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2018.09.009","article-title":"In vivo fate and activity of second- versus third-generation CD19-specific CAR-T cells in B cell non-hodgkin\u2019s lymphomas","volume":"26","author":"Ramos","year":"2018","journal-title":"Mol Ther"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-021-00244-2","article-title":"Dual targeting CAR-T cells with optimal costimulation and metabolic fitness enhance antitumor activity and prevent escape in solid tumors","volume":"2","author":"Hirabayashi","year":"2021","journal-title":"Nat Cancer"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830271006","article-title":"Ligation of the T cell co-stimulatory receptor CD28 activates the serine-threonine protein kinase protein kinase B","author":"Parry","year":"1997","journal-title":"Eur J Immunol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1084\/jem.179.3.1071","article-title":"Stimulation of CD28 triggers an association between CD28 and phosphatidylinositol 3-kinase in Jurkat T cells","author":"Truitt","year":"1994","journal-title":"J Exp Med"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1172\/JCI133215","article-title":"Single residue in CD28-costimulated CAR-T cells limits long-term persistence and antitumor durability","author":"Guedan","year":"2020","journal-title":"J Clin Invest"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2011.08072.x","article-title":"Tec family kinases Itk and Rlk\/Txk in T lymphocytes: cross-regulation of cytokine production and T-cell fates","author":"Gomez-Rodriguez","year":"2011","journal-title":"FEBS J"},{"key":"B57","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1126\/scisignal.aat6753","article-title":"Phosphoproteomic analysis of chimeric antigen receptor signaling reveals kinetic and quantitative differences that affect cell function","author":"Salter","year":"2018","journal-title":"Sci Signaling"},{"key":"B58","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1182\/blood-2018-99-110645","article-title":"Mutation of the CD28 costimulatory domain confers decreased CAR T cell exhaustion","volume":"132","author":"Boucher","year":"2018","journal-title":"Blood"},{"key":"B59","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1182\/blood-2019-122954","article-title":"Mutation of the CD28 co-stimulatory domain confers enhanced CAR T cell function","volume":"134","author":"Boucher","year":"2019","journal-title":"Blood"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1089\/hgtb.2016.153","article-title":"CAR T-cell therapy: progress and prospects","author":"Wilkins","year":"2017","journal-title":"Hum Gene Ther Methods"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1456443\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T06:22:09Z","timestamp":1734070929000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1456443\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,13]]},"references-count":60,"alternative-id":["10.3389\/fimmu.2024.1456443"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1456443","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,13]]},"article-number":"1456443"}}