The BCR-ABL inhibitor nilotinib influences phenotype and function of monocyte-derived human dendritic cells

Autor: Susanne M. Rittig, Christian J. Lechner, Stefanie Maurer, Michael Gutknecht, Daniela Dörfel, Julian Geiger, Korbinian N. Kropp, Helmut R. Salih, Hans-Georg Kopp, Tanja Funk, Martin Müller, Simone Joas, Julia Salih, Frank Grünebach
Rok vydání: 2018
Předmět:
Zdroj: Cancer Immunology, Immunotherapy. 67:775-783
ISSN: 1432-0851
0340-7004
DOI: 10.1007/s00262-018-2129-9
Popis: In chronic myeloid leukemia (CML), the translocation t(9;22) results in the fusion protein BCR-ABL (breakpoint cluster region-abelson murine leukemia), a tyrosine kinase mediating oncogenic signaling which is successfully targeted by treatment with BCR-ABL inhibitors like imatinib. However, BCR-ABL inhibitors may also affect antitumor immunity. For instance, it was reported that imatinib impairs the function of dendritic cells (DCs) that play a central role in initiating and sustaining T cell responses. Meanwhile, second generation BCR-ABL inhibitors like nilotinib, which inhibits BCR-ABL with enhanced potency have become standard of treatment, at least in patients with BCR-ABL kinase domain mutations. In this study we analyzed the influence of therapeutic concentrations of nilotinib on human monocyte-derived DCs and compared its effects to imatinib. We found that both tyrosine kinase inhibitors (TKI) comparably and significantly impaired differentiation of monocytes to DCs as revealed by curtated downregulation of CD14 and reduced upregulation of CD1a and CD83. This was only partially restored after withdrawal of the TKI. Moreover, both TKI significantly reduced activation-induced IL-12p70 and C-C motif chemokine ligand (CCL) 3 secretion, while divergent TKI effects for CCL2 and CCL5 were observed. In contrast, only nilotinib significantly impaired the migratory capacity of DCs and their capacity to induce T-cell immune responses in MLRs. Our results indicate that imatinib and nilotinib may differ significantly with regard to their influence on antitumor immunity. Thus, for future combinatory approaches and particularly stop studies in CML treatment, choice of the most suitable BCR-ABL inhibitor requires careful consideration.
Databáze: OpenAIRE
Externí odkaz: