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The BCR/ABL‐inhibitors imatinib, nilotinib and dasatinib differentially affect NK cell reactivity
Author(s) -
Salih Julia,
Hilpert Julia,
Placke Theresa,
Grünebach Frank,
Steinle Alexander,
Salih Helmut Rainer,
Krusch Matthias
Publication year - 2010
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25233
Subject(s) - nilotinib , dasatinib , cancer research , imatinib , k562 cells , myeloid leukemia , cytokine , tyrosine kinase , natural killer cell , imatinib mesylate , biology , cytotoxicity , immunology , leukemia , signal transduction , microbiology and biotechnology , in vitro , biochemistry
In chronic myeloid leukemia (CML), BCR/ABL‐mediated oncogenic signaling can be targeted with the BCR/ABL‐inhibitors Imatinib, Nilotinib and Dasatinib. However, these agents may also affect anti‐tumor immunity. Here, we analyzed the effects of the 3 BCR/ABL‐inhibitors on natural killer (NK) cell reactivity. Exposure of CML cells (K562, Meg‐01) to pharmacological concentrations of Imatinib, Nilotinib and Dasatinib diminished expression of ligands for the activating immunoreceptor NKG2D to a similar extent. This resulted in comparably reduced NK cell cytotoxicity and IFN‐γ production. When direct effects on NK cell responses to K562 and primary CML cells as well as activating cytokines were studied, Dasatinib was found to abrogate NK cytotoxicity and cytokine production. Nilotinib did not alter cytotoxicity but, at high levels, impaired NK cytokine production, while Imatinib had no direct influence on NK cell reactivity. Of note, Nilotinib, but not the other BCR/ABL‐inhibitors increased cell death within the preferentially cytokine‐secreting CD56 bright CD16 − NK cell subset, which may, at least in part, serve to explain the effect of Nilotinib on NK cytokine production. Analysis of NK cell signaling revealed that Dasatinib inhibited proximal signaling events leading to decreased phosphorylation of PI3K and ERK that are crucial for NK cell reactivity. Imatinib and Nilotinib, in contrast, showed no relevant effect on NK cell PI3K or ERK activity. In light of the potential role of NK cells in the immunesurveillance of residual leukemia and for future combinatory immunotherapeutic approaches, our data indicate that choice and dosing of the most suitable BCR/ABL‐inhibitor for a given patient require careful consideration.