Monocyte-to-macrophage switch reversibly impaired by Ibrutinib
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Isacco Ferrarini1,2,*, Antonella Rigo1,2,*, Alessio Montresor1,3, Carlo Laudanna1,3 and Fabrizio Vinante1,2
1Department of Medicine, University of Verona, Verona, Italy
2Section of Hematology, Cancer Research & Cell Biology Laboratory, University of Verona, Verona, Italy
3Division of General Pathology, University of Verona, Verona, Italy
*These authors contributed equally to this work and share co-first authorship
Isacco Ferrarini, email: [email protected]
Keywords: Ibrutinib; monocyte; macrophage differentiation; fibrocyte-like cells; adhesion
Received: October 19, 2018 Accepted: February 19, 2019 Published: March 08, 2019
Ibrutinib is increasingly adopted for treating lymphoid malignancies. While growing amounts of data pile up about Ibrutinib mechanism of action on neoplastic B cells, little is known about its impact on other immune cells.
Here we investigated the effect of Ibrutinib on monocyte/macrophage functions. (1) Ibrutinib treatment of purified human monocytes affected both chemoattractant-triggered inside-out as well as integrin-mediated outside-in signaling events, thus provoking defective adhesion and spreading on purified integrin ligands, respectively. (2) In in vitro cell-culture experiments, Ibrutinib promoted a differentiation shift of monocytes to fibrocyte-like cells, characterized by the acquisition of a typical elongated cell morphology. Importantly, this clear-cut shape transition also occurred upon culturing monocytes with sera derived from Ibrutinib-treated patients, thus clearly suggesting that the drug concentrations achievable in vivo can generate the phenotypic shift. (3) Ibrutinib-induced fibrocyte-like cells showed adhesion deficiency, altered phagocytic properties, and, with respect to macrophages, they acquired the capability of generating larger amounts of reactive oxygen species, possibly displaying different metabolic activities.
Taken together, our results indicate that Ibrutinib has profound effects on the monocyte/macrophage immunobiology. They may finally shed some light about the biological ground of several Ibrutinib-related toxicities.
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