Ferrarini Isacco, Rigo Antonella, Montresor Alessio, Laudanna Carlo, Vinante Fabrizio
Department of Medicine, University of Verona, Verona, Italy.
Section of Hematology, Cancer Research & Cell Biology Laboratory, University of Verona, Verona, Italy.
Oncotarget. 2019 Mar 8;10(20):1943-1956. doi: 10.18632/oncotarget.26744.
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 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 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.
伊布替尼越来越多地被用于治疗淋巴系统恶性肿瘤。尽管关于伊布替尼对肿瘤性B细胞作用机制的数据越来越多，但对于其对其他免疫细胞的影响却知之甚少。在此，我们研究了伊布替尼对单核细胞/巨噬细胞功能的影响。（1）用伊布替尼处理纯化的人单核细胞，会影响趋化因子触发的由内向外以及整合素介导的由外向内信号转导事件，从而分别导致在纯化的整合素配体上的黏附缺陷和铺展缺陷。（2）在细胞培养实验中，伊布替尼促使单核细胞向成纤维细胞样细胞分化转变，其特征是获得典型的细长细胞形态。重要的是，在用伊布替尼治疗的患者血清培养单核细胞时也会出现这种明显的形态转变，这清楚地表明可达到的药物浓度能够产生这种表型转变。（3）伊布替尼诱导的成纤维细胞样细胞表现出黏附缺陷、吞噬特性改变，并且相对于巨噬细胞，它们获得了产生大量活性氧的能力，可能显示出不同的代谢活性。综上所述，我们的结果表明伊布替尼对单核细胞/巨噬细胞免疫生物学有深远影响。它们最终可能会揭示一些与伊布替尼相关毒性的生物学基础。
