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A Small Molecule Antagonist of CX3CR1 (KAND567) Inhibited the Tumor Growth-Promoting Effect of Monocytes in Chronic Lymphocytic Leukemia (CLL). | LitMetric
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 ( = 88) than in healthy donors ( = 32) ( < 0.0001), with higher levels in patients with active compared to non-active disease ( < 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 ( < 0.001), particularly in those with active disease ( < 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 ( < 0.05). Additionally, KAND567 inhibited the transition of monocytes to NLCs in CLL ( < 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.
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