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Imatinib and Nilotinib Off-Target Effects on Human NK Cells, Monocytes, and M2 Macrophages.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2017 Aug 15; Vol. 199 (4), pp. 1516-1525. Date of Electronic Publication: 2017 Jul 12. - Publication Year :
- 2017
-
Abstract
- Tyrosine kinase inhibitors (TKIs) are used in the clinical management of hematological neoplasms. Moreover, in solid tumors such as stage 4 neuroblastomas (NB), imatinib showed benefits that might depend on both on-target and immunological off-target effects. We investigated the effects of imatinib and nilotinib on human NK cells, monocytes, and macrophages. High numbers of monocytes died upon exposure to TKI concentrations similar to those achieved in patients. Conversely, NK cells were highly resistant to the TKI cytotoxic effect, were properly activated by immunostimulatory cytokines, and degranulated in the presence of NB cells. In NB, neither drug reduced the expression of ligands for activating NK receptors or upregulated that of HLA class I, B7-H3, PD-L1, and PD-L2, molecules that might limit NK cell function. Interestingly, TKIs modulated the chemokine receptor repertoire of immune cells. Acting at the transcriptional level, they increased the surface expression of CXCR4, an effect observed also in NK cells and monocytes of patients receiving imatinib for chronic myeloid leukemia. Moreover, TKIs reduced the expression of CXCR3 (in NK cells) and CCR1 (in monocytes). Monocytes also decreased the expression of M-CSFR, and low numbers of cells underwent differentiation toward macrophages. M0 and M2 macrophages were highly resistant to TKIs and maintained their phenotypic and functional characteristics. Importantly, also in the presence of TKIs, the M2 immunosuppressive polarization was reverted by TLR engagement, and M1-oriented macrophages fully activated autologous NK cells. Our results contribute to better interpreting the off-target efficacy of TKIs in tumors and to envisaging strategies aimed at facilitating antitumor immune responses.<br /> (Copyright © 2017 by The American Association of Immunologists, Inc.)
- Subjects :
- B7-H1 Antigen genetics
B7-H1 Antigen metabolism
Cell Differentiation drug effects
Cytokines immunology
Cytokines metabolism
Humans
Killer Cells, Natural immunology
Killer Cells, Natural physiology
Lymphocyte Activation drug effects
Macrophages immunology
Macrophages physiology
Monocytes immunology
Monocytes physiology
Neuroblastoma immunology
Programmed Cell Death 1 Ligand 2 Protein genetics
Programmed Cell Death 1 Ligand 2 Protein metabolism
Receptors, CCR1 genetics
Receptors, CCR1 immunology
Receptors, CCR1 metabolism
Receptors, CXCR3 genetics
Receptors, CXCR3 metabolism
Receptors, CXCR4 genetics
Receptors, CXCR4 metabolism
Antineoplastic Agents pharmacology
Imatinib Mesylate pharmacology
Killer Cells, Natural drug effects
Macrophages drug effects
Monocytes drug effects
Pyrimidines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 199
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 28701512
- Full Text :
- https://doi.org/10.4049/jimmunol.1601695