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PMID: 18981115 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Journal of immunology (Baltimore, Md. : 1950) ·Vol. 181 ·No. 10 ·2008-11-15 ·Pages 6955-63

Larmonier N, Janikashvili N, LaCasse CJ, Larmonier CB, Cantrell J, Situ E, Lundeen T, Bonnotte B, Katsanis E

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.

MeSH Terms
Animals Antineoplastic Agents/administration & dosage Benzamides Blotting, Western Cancer Vaccines/immunology,therapeutic use Cell Line, Tumor Cell Proliferation/drug effects Combined Modality Therapy Dendritic Cells/transplantation Enzyme-Linked Immunosorbent Assay Female Flow Cytometry Forkhead Transcription Factors/biosynthesis,drug effects Imatinib Mesylate Immunohistochemistry Immunotherapy, Active/methods Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology,therapy Mice Mice, Inbred BALB C Phosphorylation/drug effects Piperazines/administration & dosage Pyrimidines/administration & dosage STAT3 Transcription Factor/drug effects,metabolism STAT5 Transcription Factor/drug effects,metabolism T-Lymphocytes, Regulatory/drug effects,immunology
Chemicals
Antineoplastic Agents Benzamides Cancer Vaccines Forkhead Transcription Factors Foxp3 protein, mouse Piperazines Pyrimidines STAT3 Transcription Factor STAT5 Transcription Factor Stat3 protein, mouse Imatinib Mesylate
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Larmonier Nicolas
Department of Pediatrics, Steele Children's Research Center, University of Arizona, Tucson, AZ 85724, USA. [email protected]
Janikashvili Nona
LaCasse Collin James
Larmonier Claire Billerey
Cantrell Jessica
Situ Elaine
Lundeen Tamara
Bonnotte Bernard
Katsanis Emmanuel
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Article Info
Journal
Journal of immunology (Baltimore, Md. : 1950)
Abbr.
J Immunol
ISSN
1550-6606
DOI
10.4049/jimmunol.181.10.6955
Email
[email protected]
Published
2008-11-15
Pages
6955-63
Language
English
Region
United States
NLM ID
2985117R
PMCID
PMC2579962
Subset
IM
Grants
NCI NIH HHS · R01 CA104926 · United States
NCI NIH HHS · R01 CA104926-04 · United States
External Links
PubMed source DOI: 10.4049/jimmunol.181.10.6955 PMC Full Text View journal details
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