CX3CR1的小分子拮抗剂（KAND567）抑制慢性淋巴细胞白血病（CLL）中单核细胞的促肿瘤生长作用。

A Small Molecule Antagonist of CX3CR1 (KAND567) Inhibited the Tumor Growth-Promoting Effect of Monocytes in Chronic Lymphocytic Leukemia (CLL).

作者信息

Zhong Wen, Kokhaei Parviz, Mulder Tom A, Ghaderi Amineh, Moshfegh Ali, Lundin Jeanette, Palma Marzia, Schultz Johan, Olin Thomas, Österborg Anders, Mellstedt Håkan, Hojjat-Farsangi Mohammad

机构信息

Department of Oncology-Pathology, BioClinicum, Karolinska University Hospital, Solna, Stockholm and Karolinska Institute, SE-17176 Stockholm, Sweden.

Department of Immunology, Arak University of Medical Sciences, Arak 3848170001, Iran.

出版信息

Cancers (Basel). 2024 Nov 13;16(22):3821. doi: 10.3390/cancers16223821.

DOI:10.3390/cancers16223821

PMID:39594776

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11592364/

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 ( = 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.

摘要

背景/目的：肿瘤微环境中源自单核细胞的类护士细胞（NLCs）支持慢性淋巴细胞白血病（CLL）细胞的生长。在此，我们研究了CX3CR1（趋化因子受体）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

通过酶联免疫吸附测定法（ELISA）测定CX3CL1的血浆浓度，通过流式细胞术测定CX3CR1的表达。来自CLL患者和健康供体的CD19细胞和自体单核细胞，分别在共培养或单独培养条件下用KAND567处理。通过膜联蛋白V/碘化丙啶（Annexin V/PI）染色和活细胞成像确定CD19细胞和单核细胞的凋亡情况。

结果

CLL患者（n = 88）的血浆CX3CL1（趋化因子）浓度显著高于健康供体（n = 32）（P < 0.0001），与非活动性疾病患者相比，活动性疾病患者的CX3CL1水平更高（P < 0.01）。在患者和对照中，CX3CR1在单核细胞而非B细胞上被发现。CLL患者中中间型和非经典型CX3CR1单核细胞的水平高于对照（P < 0.001），特别是在活动性疾病患者中（P < 0.0001）。共培养实验表明，自体单核细胞促进恶性和正常B细胞的存活，并且KAND567以剂量依赖方式选择性抑制CLL细胞的生长，但仅在存在自体单核细胞的情况下（P < 0.05）。此外，KAND567抑制CLL中单核细胞向NLCs的转变（P < 0.05）。