{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T06:06:37Z","timestamp":1791180397698,"version":"4.1.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2008,11,1]],"date-time":"2008-11-01T00:00:00Z","timestamp":1225497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Imatinib mesylate (Gleevec, STI571), a selective inhibitor of a restricted number of tyrosine kinases, has been effectively used for the treatment of Philadelphia chromosome-positive leukemias and gastrointestinal stromal tumors. Imatinib may also directly influence immune cells. Suppressive as well as stimulating effects of this drug on CD4+ and CD8+ T lymphocytes or dendritic cells have been reported. In the current study, we have investigated the influence of imatinib mesylate on CD4+CD25+FoxP3+ regulatory T cells (Treg), a critical population of lymphocytes that contributes to peripheral tolerance. Used at concentrations achieved clinically, imatinib impaired Treg immunosuppressive function and FoxP3 expression but not production of IL-10 and TGF-\u03b2 in vitro. Imatinib significantly reduced the activation of the transcription factors STAT3 and STAT5 in Treg. Analysis of Treg TCR-induced signaling cascade indicated that imatinib inhibited phosphorylation of ZAP70 and LAT. Substantiating these observations, imatinib treatment of mice decreased Treg frequency and impaired their immunosuppressive function in vivo. Furthermore, imatinib mesylate significantly enhanced antitumor immune responses to dendritic cell-based immunization against an imatinib-resistant BCR-ABL negative lymphoma. The clinical applications of imatinib mesylate might thus be expanded with its use as a potent immunomodulatory agent targeting Treg in cancer immunotherapy.<\/jats:p>","DOI":"10.4049\/jimmunol.181.10.6955","type":"journal-article","created":{"date-parts":[[2014,4,18]],"date-time":"2014-04-18T23:00:36Z","timestamp":1397862036000},"page":"6955-6963","source":"Crossref","is-referenced-by-count":141,"title":["Imatinib Mesylate Inhibits CD4+CD25+ Regulatory T Cell Activity and Enhances Active Immunotherapy against BCR-ABL\u2212 Tumors"],"prefix":"10.1093","volume":"181","author":[{"given":"Nicolas","family":"Larmonier","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Steele Children\u2019s Research Center"},{"name":"Department of Immunobiology"},{"name":"BIO5 Institute and Arizona Cancer Center, University of Arizona , Tucson, AZ 85724"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nona","family":"Janikashvili","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Steele Children\u2019s Research Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Collin James","family":"LaCasse","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Steele Children\u2019s Research Center"},{"name":"Department of Immunobiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire Billerey","family":"Larmonier","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Steele Children\u2019s Research Center"},{"name":"Department of Immunobiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Cantrell","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Steele Children\u2019s Research Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"Situ","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Steele Children\u2019s Research Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Lundeen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Steele Children\u2019s Research Center"},{"name":"Department of Immunobiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Bonnotte","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, Unit\u00e9 Mixte de Recherche, IFR, Faculty of Medicine , Dijon,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Katsanis","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Steele Children\u2019s Research Center"},{"name":"Department of Immunobiology"},{"name":"BIO5 Institute and Arizona Cancer Center, University of Arizona , Tucson, AZ 85724"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2008,11,15]]},"reference":[{"key":"2025032719185039500_R1","first-page":"3","article-title":"Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia","volume-title":"J. Clin. Invest.","year":"2000"},{"key":"2025032719185039500_R2","first-page":"683","article-title":"Imatinib mesylate: a new oral targeted therapy","volume-title":"N. Engl. J. 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Immunother.","year":"2007"},{"key":"2025032719185039500_R8","first-page":"747","article-title":"Imatinib mesylate minimally affects bcr-abl+ and normal monocyte-derived dendritic cells but strongly inhibits T cell expansion despite reciprocal dendritic cell-T cell activation","volume-title":"J. Leukocyte Biol.","year":"2006"},{"key":"2025032719185039500_R9","first-page":"1905","article-title":"Imatinib mesylate suppresses cytokine synthesis by activated CD4 T cells of patients with chronic myelogenous leukemia","volume-title":"Leukemia","year":"2005"},{"key":"2025032719185039500_R10","first-page":"1928","article-title":"Effects of imatinib on monocyte-derived dendritic cells are mediated by inhibition of nuclear factor-\u03baB and Akt signaling pathways","volume-title":"Clin. 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Clin. Invest.","year":"2004"},{"key":"2025032719185039500_R16","first-page":"8","article-title":"Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease","volume-title":"Immunol. Rev.","year":"2006"},{"key":"2025032719185039500_R17","first-page":"389","article-title":"CD4+ CD25+ suppressor T cells: more questions than answers","volume-title":"Nat. Rev. Immunol.","year":"2002"},{"key":"2025032719185039500_R18","first-page":"2591","article-title":"CD8+ T cell immunity against a tumor\/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells","volume-title":"J. Immunol.","year":"2005"},{"key":"2025032719185039500_R19","first-page":"455","article-title":"Regulatory T cells: key controllers of immunologic self-tolerance","volume-title":"Cell","year":"2000"},{"key":"2025032719185039500_R20","first-page":"336","article-title":"CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative","volume-title":"Eur. J. Immunol.","year":"2004"},{"key":"2025032719185039500_R21","first-page":"2756","article-title":"Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma","volume-title":"J. Immunol.","year":"2002"},{"key":"2025032719185039500_R22","first-page":"1444","article-title":"Foxp3 expressing CD4+CD25high regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells","volume-title":"J. 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Leukocyte Biol.","year":"2008"},{"key":"2025032719185039500_R27","first-page":"90","article-title":"Dendritic cells loaded with stressed tumor cells elicit long-lasting protective tumor immunity in mice depleted of CD4+CD25+ regulatory T cells","volume-title":"J. Immunol.","year":"2005"},{"key":"2025032719185039500_R28","first-page":"3623","article-title":"Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells","volume-title":"J. Clin. Invest.","year":"2005"},{"key":"2025032719185039500_R29","first-page":"208","article-title":"Selective elimination of human regulatory T lymphocytes in vitro with the recombinant immunotoxin LMB-2","volume-title":"J. Immunother.","year":"2006"},{"key":"2025032719185039500_R30","first-page":"2845","article-title":"Triggering of OX40 (CD134) on CD4+CD25+ T cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR","volume-title":"Blood","year":"2005"},{"key":"2025032719185039500_R31","first-page":"1750","article-title":"CD25+ regulatory T cell depletion augments immunotherapy of micrometastases by an IL-21-secreting cellular vaccine","volume-title":"J. Immunol.","year":"2006"},{"key":"2025032719185039500_R32","first-page":"331","article-title":"A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3","volume-title":"Nat. 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Cancer Res.","year":"2005"},{"key":"2025032719185039500_R48","first-page":"4485","article-title":"Tumor-derived, chaperone-rich cell lysate activates dendritic cells and elicits potent antitumor immunity","volume-title":"Blood","year":"2003"},{"key":"2025032719185039500_R49","first-page":"142","article-title":"Imatinib does not impair specific antitumor T-cell immunity in patients with chronic myeloid leukemia","volume-title":"Leukemia","year":"2006"},{"key":"2025032719185039500_R50","first-page":"5342","article-title":"Development and dynamics of robust T-cell responses to CML under imatinib treatment","volume-title":"Blood","year":"2008"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/181\/10\/6955\/62582226\/8083.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/181\/10\/6955\/62582226\/8083.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T18:14:41Z","timestamp":1743358481000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/181\/10\/6955\/8007940"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,11]]},"references-count":50,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2008,11,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.181.10.6955","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"value":"1550-6606","type":"electronic"},{"value":"0022-1767","type":"print"}],"subject":[],"published-other":{"date-parts":[[2008,11]]},"published":{"date-parts":[[2008,11]]}}}