title: 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.
abstract: 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 CD14low 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.
authors.affiliation: Laboratoire d'Immunologie et Histocompatibilité, INSERM U662, Institut Universitaire d'Hématologie, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Boissel
authors.forename: Philippe
authors.initials: P
authors.lastname: Rousselot
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Raffoux
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Cayuela
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.forename: Nuala
authors.initials: N
authors.lastname: Mooney
authors.forename: Dominique
authors.initials: D
authors.lastname: Charron
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
authors.forename: Antoine
authors.initials: A
authors.lastname: Toubert
authors.forename: Delphine
authors.initials: D
authors.lastname: Rea
mesh_terms: D000328:Adult; D001549:Benzamides; D002454:Cell Differentiation / Q000276:immunology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D016044:Fusion Proteins, bcr-abl / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D000068877:Imatinib Mesylate; D007159:Immunologic Tests; D018664:Interleukin-12 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D013997:Time Factors
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D018664:Interleukin-12; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl