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Imatinib Mesylate Inhibits CD4⁺CD25⁺ Regulatory T Cell Activity and Enhances Active Immunotherapy against BCR-ABL^– Tumors¹

Nicolas Larmonier^2,*,,, Nona Janikashvili^*, Collin James LaCasse^*,, Claire Billerey Larmonier^*,, Jessica Cantrell^*, Elaine Situ^*, Tamara Lundeen^*,, Bernard Bonnotte and Emmanuel Katsanis^*,,

^* Department of Pediatrics, Steele Children’s Research Center, Department of Immunobiology, and BIO5 Institute and Arizona Cancer Center, University of Arizona, Tucson, AZ 85724; and Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche, IFR, Faculty of Medicine, Dijon, France

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by the National Institutes of Health Grant R01 CA104926, the Leukemia and Lymphoma Society Fellow Award 5188-07 (to N.L.), the Tee Up for Tots, and Raise a Racquet for Kids Funds.

² Address correspondence and reprint requests to Dr. Nicolas Larmonier, University of Arizona, Department of Pediatrics, 1501 North Campbell Avenue, PO Box 245073, Tucson, Arizona 85724-5073. E-mail address: nrlarmon{at}email.arizona.edu

³ Abbreviations used in this paper: CML, chronic myelogenous leukemia; DC, dendritic cell; Treg, regulatory T cell; ABL, Abelson; LAT, linker of activation of T cell; FoxP3, Forkhead box P3; Lck, leukocyte-specific protein tyrosine kinase.

⁴ The online version of this article contains supplemental material.