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

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.