The CC chemokine receptor 4 as a novel specific molecular target for immunotherapy in adult T-cell leukemia/lymphoma
The CC chemokine receptor 4 as a novel specific molecular target for immunotherapy in adult T-cell leukemia/lymphoma
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DOI：
10.1158/1078-0432.ccr-04-0983
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发表时间：
2004-11-15
影响因子：
11.5
通讯作者：
Ueda, R
中科院分区：
文献类型：
--
作者：
Ishida, T;Iida, S;Ueda, R
成人T细胞白血病/淋巴瘤（ATLL）是一种预后不良的外周T细胞肿瘤，目前尚无最佳治疗方法。我们测试了去岩藻糖基化嵌合抗CC趋化因子受体4（CCR 4）单克隆抗体，KM 2760，以开发一种新的免疫治疗这种难治性肿瘤。在来自健康成人供体的外周血单核细胞（PBMC）存在下，KM 2760诱导针对CCR 4阳性ATLL细胞系和从ATLL患者获得的原代肿瘤细胞的CCR 4特异性抗体依赖性细胞毒性（ADCC）。我们接下来在自体环境中检查了KM 2760诱导的针对原代ATLL细胞的ADCC。自体效应细胞介导的抗体依赖性细胞毒性通常低于同种异体对照效应细胞介导的细胞毒性。然而，在某些情况下诱导了强大的ADCC活性，这与同种异体效应细胞介导的活性相当。这表明ATLL患者的PBMC保留了大量的ADCC效应器功能，尽管尚未确定最大效果的最佳条件。此外，我们还发现ATLL细胞中高表达FoxP 3 mRNA和蛋白，这是调节性T细胞的标志，表明ATLL细胞可能起源于调节性T细胞。在体外，KM 2760通过裂解CCR 4（+）T细胞降低正常PBMC中FoxP 3 mRNA的表达，同时沿着CCR 4 mRNA的表达。我们的数据表明，不仅CCR 4分子可能是一个合适的目标，为新的抗体为基础的治疗与ATLL患者，而且，KM 2760可能会通过减少调节性T细胞的数量诱导有效的肿瘤免疫。
Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell neoplasm with dismal prognosis, and no optimal therapy has been developed. We tested the defucosylated chimeric anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, KM2760, to develop a novel immunotherapy for this refractory tumor. In the presence of peripheral blood mononuclear cells (PBMCs) from healthy adult donors, KM2760 induced CCR4-specific antibody-dependent cellular cytotoxicity (ADCC) against CCR4-positive ATLL cell lines and primary tumor cells obtained from ATLL patients. We next examined the KM2760-induced ADCC against primary ATLL cells in an autologous setting. Antibody-dependent cellular cytotoxicity mediated by autologous effector cells was generally lower than that mediated by allogeneic control effector cells. However, a robust ADCC activity was induced in some cases, which was comparable with that mediated by allogeneic effector cells. It suggests that the ATLL patients' PBMCs retain substantial ADCC-effector function, although the optimal conditions for maximal effect have not yet been determined. In addition, we also found a high expression of FoxP3 mRNA and protein, a hallmark of regulatory T cells, in ATLL cells, indicating the possibility that ATLL cells originated from regulatory T cells. KM2760 reduced FoxP3 mRNA expression in normal PBMCs along with CCR4 mRNA by lysis of CCR4(+) T cells in vitro. Our data suggest not only that the CCR4 molecule could be a suitable target for the novel antibody-based therapy for patients with ATLL but also that KM2760 may induce effective tumor immunity by reducing the number of regulatory T cells.