CD44v10, osteopontin and lymphoma growth retardation by a CD44v10-specific antibody
CD44v10, osteopontin and lymphoma growth retardation by a CD44v10-specific antibody
复制标题
DOI：
10.1038/icb.2014.47
复制
发表时间：
2014-09-01
影响因子：
4
通讯作者：
Zoeller, Margot
中科院分区：
文献类型：
--
作者：
Megaptche, Amelie Pajip;Erb, Ulrike;Zoeller, Margot
阻断CD44被认为是消除白血病启动细胞的一种治疗选择。然而，抗PanCD44的应用可能会产生严重的副作用。我们以EL4胸腺瘤和转CD44v10的EL4(EL4-V10)为模型，确定在CD44v阳性的血液系统恶性肿瘤中，用CD44变异异构体(CD44v)特异性抗体替换抗panCD44是否可以避免这些副作用。抗PanCD44和抗CD44v10抗体对EL4和EL4-V10的皮下生长均有同样好的抑制作用。体外分析表明，自然杀伤细胞毒性和抗体依赖性细胞毒性是其主要作用机制。在局部炎症情况下，抗CD44v10抗体的疗效是未经治疗的EL4-V10荷瘤小鼠的两倍，这是由于炎症诱导骨桥蛋白(OPN)的表达。EL4-V10肿瘤中高水平的OPN支持白细胞募集和肿瘤浸润性T细胞激活。综上所述，在表达CD44v的恶性血液病中，抗PanCD44可以被CD44v特异性抗体取代而不会失去疗效。此外，CD44v10特异性抗体在皮肤白血病治疗中似乎特别有利，因为OPN的CD44v10结合推动了白细胞的募集和激活。
Blockade of CD44 is considered a therapeutic option for the elimination of leukemia-initiating cells. However, the application of anti-panCD44 can be burdened by severe side effects. We determined whether these side effects could be avoided by replacing anti-panCD44 with CD44 variant isoform (CD44v)-specific antibodies in CD44v-positive hematological malignancies using the EL4 thymoma and CD44v10-transfected EL4 (EL4-v10) as models. Subcutaneous growth of EL4 and EL4-v10 was equally well inhibited by the anti-panCD44 and anti-CD44v10 antibodies, respectively. Ex vivo analysis indicated that natural killer cytotoxicity and antibody-dependent cellular cytotoxicity were the main effector mechanisms. Under local inflammation, the efficacy of anti-CD44v10 prolonged the survival time twofold compared with untreated, EL4-v10 tumor-bearing mice, and this was due to inflammation-induced expression of osteopontin (OPN). A high level of OPN in EL4-v10 tumors supported leukocyte recruitment and tumor-infiltrating T-cell activation. Taken together, in hematological malignancies expressing CD44v, anti-panCD44 can be replaced by CD44v-specific antibodies without a loss in efficacy. Furthermore, CD44v10-specific antibodies appear particularly advantageous in cutaneous leukemia therapy, as CD44v10 binding of OPN drives leukocyte recruitment and activation.