title: Imatinib mesylate inhibits CD4+ CD25+ regulatory T cell activity and enhances active immunotherapy against BCR-ABL- tumors.
abstract: 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-beta 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.
authors.affiliation: Department of Pediatrics, Steele Children's Research Center, University of Arizona, Tucson, AZ 85724, USA. nrlarmon@email.arizona.edu
authors.forename: Nicolas
authors.initials: N
authors.lastname: Larmonier
authors.forename: Nona
authors.initials: N
authors.lastname: Janikashvili
authors.forename: Collin James
authors.initials: CJ
authors.lastname: LaCasse
authors.forename: Claire Billerey
authors.initials: CB
authors.lastname: Larmonier
authors.forename: Jessica
authors.initials: J
authors.lastname: Cantrell
authors.forename: Elaine
authors.initials: E
authors.lastname: Situ
authors.forename: Tamara
authors.initials: T
authors.lastname: Lundeen
authors.forename: Bernard
authors.initials: B
authors.lastname: Bonnotte
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Katsanis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001549:Benzamides; D015153:Blotting, Western; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000637:transplantation*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000187:drug effects; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D016233:Immunotherapy, Active / Q000379:methods*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000187:drug effects / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D019496:Cancer Vaccines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D010879:Piperazines; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; D000068877:Imatinib Mesylate