Imatinib and Nilotinib Off-Target Effects on Human NK Cells, Monocytes, and M2 Macrophages

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.

Nilotinib activates endothelial TLR4 to exacerbate atherosclerosis

“…Therefore, leukocytes are unlikely contribute to nilotinb-exacerbated atherogenesis because they did not increase after nilotinib treatment. This observation is in line with a latest publication that nilotinib induces necrosis in monocytes and inhibits their differentiation into macrophages (26).…”

The Role of CXC Chemokine Receptors 1–4 on Immune Cells in the Tumor Microenvironment

“…In accordance, regulatory T cells are maintained within the bone marrow and can migrate along the CXCR4-CXCL12 axis ( 92 ). Regarding modulation of CXCR4 expression using pharmacological agents, tyrosine kinase inhibitors (TKIs) imatinib and nilotinib have been shown to selectively increase the cell surface of CXCR4 on NK cells and monocytes, in vitro experiments using NK cells derived from neuroblastoma patients ( 93 ).…”

Molecular Mechanisms Directing Migration and Retention of Natural Killer Cells in Human Tissues

“…Along this line, during imatinib mesylate therapy in GIST patients, the frequency of NK cells did not change in fibrous trabeculae, whereas significantly increased in the core of both localized or metastatic tumors, an observation that correlated with a better prognosis ( 78 ). Interestingly, a recent study analyzing the off-target effect of imatinib mesylate on immune cells showed that this drug causes a significant up-regulation of CXCR4 in both T and NK cells ( 86 ). Accordingly, NK cells ex-vivo isolated from peripheral blood of chronic myeloid leukemia patients receiving imatinib mesylate showed levels of CXCR4 significantly higher than those detected in healthy individuals ( 86 ).…”