Differential Effects of the BCR-ABL-Inhibitors Imatinib, Nilotinib and Dasatinib on NK Cell Reactivity against Chronic Myeloid Leukemia (CML)

Abstract

CML is characterized by the BCR-ABL fusion protein, which mediates the oncogenic signaling. This led to the development of BCR-ABL inhibitors revolutionizing therapy of CML. However, as recently reported for Dasatinib (Schade et al., Blood 111:1366 (2008); Blake et al., Blood 111:4415 (2008)), these agents may impair the activity of immune effector cells like NK cells and T cells. After initiating oncogenic events, development and progression of clinically apparent malignancy is dependent on the evasion of the tumor cells from immunosurveillance. In light of the important role of NK cell reactivity against leukemia we compared the influence of Imatinib, Nilotinib and Dasatinib on the reactivity of both resting and IL-2 activated NK cells against CML cells to identify the compound with the least immuno-compromising side effects. First, the effects of the compounds on NK cell reactivity in concentrations corresponding to plasma peak levels were studied. Dasatinib (200nM) completely abolished NK cell granule mobilization, cytotoxicity and IFN-γ production, while no substantial inhibition was observed with Imatinib (5μM) and Nilotinib (3.6μM) mediated a minor but significant inhibition (p<0.05, Student's T-test). Presence of the compounds in concentrations corresponding to IC50 levels (Imatinib 600nM, Nilotinib 30nM, Dasatinib 10nM) revealed no influence of Imatinib and Nilotinib, while Dasatinib still significantly reduced NK cell cytotoxicity and IFN-γ production up to 60%. Since Dasatinib, in addition to BCR-ABL, potently inhibits SRC kinases, which are involved in the activation of MAPK pathways and thus crucial for NK cell cytotoxicity, we determined the influence of the compounds on ERK phosphorylation. While no inhibitory effect was observed using Imatinib and Nilotinib, Dasatinib markedly reduced ERK phosphorylation in NK cells. Our data demonstrate that NK cell anti-tumor reactivity is not inhibited by clinically relevant concentrations of Imatinib. While Nilotinib may mediate a minor effect, Dasatinib substantially impairs NK cell reactivity by inhibition of signaling pathways crucial for NK cell effector functions. For a given patient, the choice and dosing of the most suitable BCR-ABL inhibitor may thus require careful consideration of its influence on the immune system, especially in view of the important role of NK cells in the immunesurveillance of residual leukemia.