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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
Author(s) -
Boissel Nicolas,
Rousselot Philippe,
Raffoux Emmanuel,
Cayuela JeanMichel,
Soulier Jean,
Mooney Nuala,
Charron Dominique,
Dombret Hervé,
Toubert Antoine,
Rea Delphine
Publication year - 2006
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0705419
Subject(s) - imatinib mesylate , dendritic cell , imatinib , biology , monocyte , abl , cancer research , cd86 , breakpoint cluster region , tyrosine kinase , t cell , microbiology and biotechnology , immunology , myeloid leukemia , antigen , signal transduction , immune system , receptor , biochemistry
In chronic myeloid leukemia, bcr‐abl + monocytes provide a unique opportunity to generate dendritic cells (DC) expressing a broad spectrum of leukemic antigens, and bcr‐abl + DC vaccines may allow immunological eradication of leukemic cells persisting under treatment with the tyrosine kinase inhibitor imatinib. However, the efficiency of bcr‐abl + DC vaccines will critically depend on the absence of deleterious effects of bcr‐abl and of imatinib on DC functions. We show that bcr‐abl + monocytes, devoid of contamination of CD14 low granulocytic precursors, differentiate into DC with typical immunophenotypical and functional features, and bcr‐abl transcription decreases simultaneously. During differentiation, imatinib induces a slight increase of DC apoptosis and prevents CD1a up‐regulation in a dose‐dependent manner in bcr‐abl + and normal monocyte‐derived DC, but at most, 25% of DC fail to acquire CD1a. When DC maturation is induced in the presence of imatinib, bcr‐abl + and normal monocyte‐derived DC up‐regulate major histocompatibility complex and costimulatory molecules, CC chemokine receptor 7 and CD83. However, secretion of interleukin‐12p70 is decreased in a dose‐dependent manner. Imatinib exposure of bcr‐abl + and normal monocyte‐derived DC during differentiation and maturation is not detrimental to T cell immunostimulatory functions of DC. In sharp contrast, imatinib, when added to DC‐T cell cultures, profoundly suppresses DC‐mediated T cell proliferation, despite reciprocal DC‐T cell activation attested by up‐regulation of CD25 on T cells and of CD86 on DC. Our findings demonstrate that T cells, not normal or bcr‐abl + monocyte‐derived DC, are major targets for imatinib immunomodulatory effects. It can be envisioned already that imatinib‐free windows will be required to enable vaccination‐induced, leukemia‐specific T cell expansion.