BCR/ABL Inhibitors Influence Phenotype and Function of Monocyte-Derived Human Dendritic Cells.

In chronic myeloid leukemia (CML) the translocation t(9;22) results in the fusion protein BCR/ABL, a tyrosine kinase that mediates oncogenic signalling, which is successfully targeted by treatment with the tyrosine kinase inhibitor (TKI), imatinib. The novel TKIs, nilotinib and dasatinib, are approved for the treatment of CML patients who progress under imatinib treatment. Therapeutic doses of TKIs also affect anti-tumor immunity. Imatinib has recently been shown to modulate differentiation of dendritic cells (DC), and dasatinib impairs effector functions of cytotoxic lymphocytes. Up to now little is known regarding possible immunomodulatory effects of dasatinib and nilotinib in DC. We here studied and compared the effects of therapeutic concentrations of the three approved TKIs on human monocyte-derived DC.

Plastic adherent peripheral blood monocytes were cultured with GM-CSF and IL-4 to generate human DC in the presence or absence of pharmacological concentrations of the drugs (nilotinib and imatinib at 1 and 3μM; dasatinib at 10 and 50nM). DC maturation was induced by adding lipopolysaccharide on day 6 of culture. The influence of treatment with the TKIs on DC was analyzed by immunostaining, determination of cytokine production, migration assays and mixed lymphocyte reaction (MLR) on day 7 of culture.

To a similar extent, all three TKIs significantly (n = 17, p<.05, Student's T test) impaired the differentiation of monocytes to DC at therapeutically relevant concentrations as revealed by reduced expression of CD1a, CD83, and the costimulatory molecules CD86 and CD80 at the cell surface. This was only partially restored after subsequent withdrawal of the TKIs from the culture. In contrast, nilotinib, but not imatinib or dasatinib significantly (n = 29, p<.05, Student's T test) impaired the migratory capacity of DC. While secretion of MIP1alpha was reduced by pharmacologically relevant doses of all three TKIs, only dasatinib reduced activation-induced secretion of further chemokines and cytokines like Rantes, MCP-1 and IL-6 (n= 8, all p<0.05, Student's T test). Moreover, pretreatment with nilotinib significantly (n=26, p<.05, Student's T test) impaired the capacity of DC to induce T-cell immune responses as revealed by MLR, while imatinib and dasatinib had no relevant influence.

Pharmacological doses of the three TKIs caused comparable phenotypic alterations of DC. Nilotinib treatment reduced DC migration and impaired the capacity of DC to induce T-cell proliferation, but did not reduce DC cytokine production except MIP1alpha. Dasatinib did not affect migration or T cell-stimulatory capacity of DC, but decreased secretion of all investigated cytokines. Importantly, in contrast to the other TKIs, imatinib did not impair any of the investigated DC functions. Since the three TKIs approved to date differ significantly with regard to their influence on immune effector functions, for future combinatory approaches using TKIs and DC-based immunotherapy, the choice and dosing of the most suitable drug requires careful consideration.

No relevant conflicts of interest to declare.