Immunoprofiling of patients with chronic myeloid leukemia at diagnosis and during tyrosine kinase inhibitor therapy
Immunoprofiling of patients with chronic myeloid leukemia at diagnosis and during tyrosine kinase inhibitor therapy
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DOI：
10.1111/j.1600-0609.2010.01501.x
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发表时间：
2010-11-01
影响因子：
3.1
通讯作者：
Mustjoki, Satu
中科院分区：
文献类型：
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作者：
Rohon, Peter;Porkka, Kimmo;Mustjoki, Satu
酪氨酸激酶抑制剂（TKIs）是目前慢性髓性白血病（CML）的标准治疗方法。除了BCR-ABL靶癌蛋白外，它们还抑制脱靶激酶（如c-KIT、TEC、SRC），其中一些激酶在免疫应答中具有生理功能。体外研究表明TKI治疗有免疫抑制作用。由于缺乏全面的体内数据，我们旨在分析CML患者在诊断和治疗期间的详细免疫谱。我们收集了54例CML患者在诊断时、伊马替尼和达沙替尼治疗期间的外周血（PB）和骨髓（BM）样本。白细胞和淋巴细胞亚类用广泛的流式细胞仪分析，包括激活、分化和记忆状态的标记。诊断时，BM中检测到B细胞和树突状细胞比例较低，nkt样细胞数量增加。在伊马替尼治疗期间，所有这些变化正常化，免疫谱与健康对照相似。然而，达沙替尼患者被明确分为两组：一组与健康对照组相似，另一组表现出免疫激活，其特征是PB中CD8+、NK-和nkt样细胞显著升高。后一组T细胞强烈表达CD57+、HLA-DR和CD45RO， CD62L抗原水平低，具有晚期记忆细胞毒性淋巴细胞的特征。我们的研究结果表明，虽然两种TKIs在体外都表现出免疫抑制作用，但它们在体内对免疫效应细胞的数量和比例有显著的不同影响。特别是，在达沙替尼治疗的患者中，免疫反应性明显增强，值得仔细随访。
Tyrosine kinase inhibitors (TKIs) are the current standard treatment in chronic myeloid leukemia (CML). In addition to the BCR-ABL target oncoprotein, they also inhibit off-target kinases (e.g. c-KIT, TEC, SRC), some of which have physiological functions in immune responses. In vitro studies have implied immunosuppressive effects of TKI treatment. As comprehensive in vivo data are missing, we aimed at analyzing the detailed immunoprofile of patients with CML at diagnosis and during therapy. We collected 88 peripheral blood (PB) and 73 bone marrow (BM) samples from 54 patients with CML at diagnosis, during imatinib and dasatinib therapies. Leukocytes and lymphocyte subclasses were analyzed with an extensive flow cytometry panel including markers for activation, differentiation and memory status. At diagnosis, a lower proportion of B cells and dendritic cells and an increased amount of NKT-like cells were detected in the BM. During imatinib therapy, all these changes normalized and the immunoprofile resembled healthy controls. However, dasatinib patients were clearly divided into two distinct groups: one similar to healthy controls and the other showing immunoactivation characterized by significant elevations of CD8+, NK- and NKT-like cells in PB. T cells of the latter group strongly expressed CD57+, HLA-DR and CD45RO and had low CD62L antigen levels characteristic of late memory cytotoxic lymphocytes. Our results indicate that while both TKIs show immunosuppressive effects in vitro, they have a significant and differential effect on the numbers and proportions of immune effector cells in vivo. In particular, in a distinct subgroup of dasatinib-treated patients, immune reactivity is markedly enhanced warranting careful follow-up.