Ishida Takashi, Inagaki Hiroshi, Utsunomiya Atae, Takatsuka Yoshifusa, Komatsu Hirokazu, Iida Shinsuke, Takeuchi Genji, Eimoto Tadaaki, Nakamura Shigeo, Ueda Ryuzo
Department of Internal Medicine & Molecular Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Clin Cancer Res. 2004 Aug 15;10(16):5494-500. doi: 10.1158/1078-0432.CCR-04-0371.
We recently reported expression of the chemokine receptors CXC chemokine receptor 3 (CXCR3) and CC chemokine receptor 4 (CCR4) in adult T-cell leukemia/lymphoma and showed a preferential expression of CCR4 and its association with an unfavorable outcome. In the present study, we extend our adult T-cell leukemia/lymphoma study to other subtypes of T- and NK-cell lymphoma, to clarify whether a characteristic chemokine receptor expression pattern is obtained for each of the subtypes defined by the WHO classification. CXCR3 and CCR4 were rarely expressed in three well-defined subtypes, precursor T-lymphoblastic lymphoma, anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, and extranodal NK/T-cell lymphoma. A CXCR3-dominant expression pattern was observed in angioimmunoblastic T-cell lymphoma, while a CCR4-dominant expression pattern was observed in mycosis fungoides in transformation and in anaplastic lymphoma kinase-negative anaplastic large cell lymphoma. CXCR3 and CCR4 were heterogeneously expressed in peripheral T-cell lymphomas, unspecified (PTCLU). We next focused on PTCLU and analyzed the clinical significance of the chemokine receptors and their association with FoxP3, a hallmark of immunoregulatory T (Treg) cells. Multivariate analysis showed that CCR4 expression was an independent and significant unfavorable prognostic factor (P < 0.001). A significant correlation was found between mRNA expression of CCR4 and FoxP3, suggesting a possible association of CCR4-positive tumors with Treg cells and thereby with an immunocompromised state. Chemokine receptors may be useful not only for further characterization of the T- and NK-cell lymphomas but also in predicting clinical outcomes for patients. We suggest that a specific therapy targeting the CCR4 molecule may be developed as an alternative treatment for patients with CCR4-positive tumors.
我们最近报道了趋化因子受体CXC趋化因子受体3（CXCR3）和CC趋化因子受体4（CCR4）在成人T细胞白血病/淋巴瘤中的表达情况，并显示CCR4有优先表达且与不良预后相关。在本研究中，我们将成人T细胞白血病/淋巴瘤的研究扩展至其他T细胞和NK细胞淋巴瘤亚型，以明确世界卫生组织（WHO）分类所定义的各亚型是否具有特征性的趋化因子受体表达模式。CXCR3和CCR4在三种明确的亚型中很少表达，即前体T淋巴母细胞淋巴瘤、间变性淋巴瘤激酶阳性的间变性大细胞淋巴瘤和结外NK/T细胞淋巴瘤。在血管免疫母细胞性T细胞淋巴瘤中观察到CXCR3占主导的表达模式，而在转化期蕈样肉芽肿和间变性淋巴瘤激酶阴性的间变性大细胞淋巴瘤中观察到CCR4占主导的表达模式。CXCR3和CCR4在外周T细胞淋巴瘤，非特指型（PTCLU）中呈异质性表达。接下来我们聚焦于PTCLU，分析趋化因子受体的临床意义及其与免疫调节性T（Treg）细胞的标志FoxP3的关联。多因素分析显示CCR4表达是一个独立且显著的不良预后因素（P < 0.001）。发现CCR4的mRNA表达与FoxP3之间存在显著相关性，提示CCR4阳性肿瘤可能与Treg细胞相关，进而与免疫受损状态相关。趋化因子受体不仅可能有助于进一步明确T细胞和NK细胞淋巴瘤的特征，还可用于预测患者的临床结局。我们建议针对CCR4分子开发特异性疗法，作为CCR4阳性肿瘤患者的替代治疗方法。
