Imatinib mesylate inhibits CD4+CD25+ regulatory T cell activity and enhances active immunotherapy against BCR-ABL- tumors

Nicolas Larmonier, Nona Janikashvili, Collin James Lacasse, Claire Billerey Larmonier, Jessica Cantrell, Elaine Situ, Tamara Lundeen, Bernard Bonnotte, Emmanuel Katsanis

Research output: Contribution to journalArticle

122 Scopus citations

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-β 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.

Original languageEnglish (US)
Pages (from-to)6955-6963
Number of pages9
JournalJournal of Immunology
Volume181
Issue number10
DOIs
StatePublished - Nov 15 2008

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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