Imatinib and Nilotinib Off-Target Effects on Human NK Cells, Monocytes, and M2 Macrophages
Francesca Bellora1, Alessandra Dondero1, Maria Valeria Corrias2
1Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, 16132 Genoa, Italy.
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.
Insights
Tyrosine kinase inhibitors (TKIs) impact immune cells, with monocytes being sensitive but NK cells resistant. TKIs alter chemokine receptors, potentially influencing anti-tumor immunity and TKI efficacy in cancers.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Tyrosine kinase inhibitors (TKIs) are crucial in treating hematological neoplasms and show promise in solid tumors like neuroblastoma (NB).
- The therapeutic benefits of TKIs may involve both direct anti-cancer effects and modulation of the immune system.
- Understanding TKI effects on immune cells is vital for optimizing cancer therapy.
Purpose of the Study:
- To investigate the impact of imatinib and nilotinib on human NK cells, monocytes, and macrophages.
- To determine how TKIs affect immune cell function and expression of key molecules in the context of neuroblastoma.
- To explore the potential of TKIs in modulating anti-tumor immune responses.
Main Methods:
- Exposure of human NK cells, monocytes, and macrophages to imatinib and nilotinib.
- Assessment of cell viability, activation markers, and degranulation.
- Analysis of cell surface molecule expression, including NK receptor ligands and chemokine receptors.
- Evaluation of macrophage polarization and their interaction with NK cells.
Main Results:
- Monocytes exhibited high susceptibility to TKIs, while NK cells demonstrated resistance and maintained activation and degranulation capabilities.
- TKIs modulated chemokine receptor expression on immune cells, increasing CXCR4 and decreasing CXCR3 and CCR1.
- Macrophages (M0 and M2) were resistant to TKIs, with M2 immunosuppression reversible by TLR engagement.
- M1 macrophages effectively activated autologous NK cells even in the presence of TKIs.
Conclusions:
- TKIs have differential effects on immune cells, impacting monocyte survival and NK cell function.
- Modulation of chemokine receptors by TKIs may influence immune cell trafficking and anti-tumor activity.
- TKIs do not inherently impair the ability of macrophages to be activated or to support NK cell function.
- These findings offer insights into the immunological off-target effects of TKIs and suggest strategies to enhance anti-tumor immunity.
