A Small Molecule Antagonist of CX3CR1 (KAND567) Inhibited the Tumor Growth-Promoting Effect of Monocytes in Chronic Lymphocytic Leukemia (CLL).
Abstract
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.
Authors: | Zhong W, Kokhaei P, Mulder TA, Ghaderi A, Moshfegh A, Lundin J, Palma M, Schultz J, Olin T, &#xd6;sterborg A, Mellstedt H, Hojjat-Farsangi M, |
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Journal: | Cancers (Basel);2024Nov13; 16 (22) . doi:10.3390/cancers16223821 |
Year: | 2024 |
PubMed: | PMID: 39594776 (Go to PubMed) |