Background/Objectives: Nurse-like cells (NLCs) derived from monocytes in the tumor microenvironment support the growth of chronic lymphocytic leukemia (CLL) cells. Here, we investigated the effects of a CX3CR1 (fractalkine receptor) antagonist (KAND567) on autologous monocytes and their pro-survival effects on CLL cells in vitro. Methods: Plasma concentration of CX3CL1 was determined by ELISA and CX3CR1 expression by flow cytometry. CD19+cells and autologous monocytes from patients with CLL and healthy donors were treated with KAND567 either in co-culture or alone. The apoptosis of CD19+cells and monocytes was determined by Annexin V/PI staining and live-cell imaging. Results: Plasma concentration of CX3CL1 (fractalkine) was significantly higher in patients with CLL (n= 88) than in healthy donors (n= 32) (p< 0.0001), with higher levels in patients with active compared to non-active disease (p< 0.01). CX3CR1 was found on monocytes but not B cells in patients and controls. Levels of intermediate and non-classical CX3CR1+monocytes were higher in patients with CLL than in controls (p< 0.001), particularly in those with active disease (p< 0.0001). Co-culture experiments revealed that autologous monocytes promoted the survival of both malignant and normal B cells and that KAND567 selectively inhibited the growth of CLL cells in a dose-dependent manner but only in the presence of autologous monocytes (p< 0.05). Additionally, KAND567 inhibited the transition of monocytes to NLCs in CLL (p< 0.05). Conclusions: Our data suggest that the CX3CR1/CX3CL1 axis is activated in CLL and may contribute to the NLC-driven growth-promoting effects of CLL cells. KAND567, which is in clinical trials in other disorders, should also be explored in CLL.
背景/目的：肿瘤微环境中单核细胞衍生的类护士细胞（NLCs）可支持慢性淋巴细胞白血病（CLL）细胞的生长。本研究探讨了CX3CR1（趋化因子Fractalkine受体）拮抗剂KAND567对自体单核细胞的影响及其在体外对CLL细胞的促生存作用。方法：采用ELISA法检测血浆CX3CL1浓度，流式细胞术分析CX3CR1表达。将CLL患者与健康供体的CD19+细胞及自体单核细胞分别进行共培养或单独培养，并给予KAND567处理。通过Annexin V/PI染色及活细胞成像技术检测CD19+细胞与单核细胞的凋亡情况。结果：CLL患者（n=88）血浆CX3CL1浓度显著高于健康供体（n=32）（p<0.0001），且活动期患者水平较非活动期更高（p<0.01）。患者与对照组中CX3CR1仅表达于单核细胞而非B细胞。CLL患者的中介型与非经典CX3CR1+单核细胞比例均高于对照组（p<0.001），活动期患者尤为显著（p<0.0001）。共培养实验显示，自体单核细胞可促进恶性与正常B细胞的存活，而KAND567仅在有自体单核细胞存在时，能剂量依赖性地选择性抑制CLL细胞生长（p<0.05）。此外，KAND567可抑制CLL患者单核细胞向NLCs的转化（p<0.05）。结论：本研究提示CX3CR1/CX3CL1轴在CLL中被激活，可能参与NLCs驱动的CLL细胞生长促进作用。已在其他疾病进入临床试验的KAND567值得在CLL领域进一步探索。
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