CCL5-Mediated Th2 Immune Polarization Promotes Metastasis in Luminal Breast Cancer
CCL5-Mediated Th2 Immune Polarization Promotes Metastasis in Luminal Breast Cancer
复制标题
CCL5介导的Th2免疫极化促进管腔乳腺癌转移
DOI：
10.1158/0008-5472.can-14-3590
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发表时间：
2015-10-15
期刊：
影响因子：
11.2
通讯作者：
Gao, Wei-Qiang
中科院分区：
文献类型：
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作者：
Zhang, Qianfei;Qin, Jilong;Gao, Wei-Qiang
肿瘤促进趋化因子CCL 5与乳腺上皮细胞的恶性转化有关，迄今为止的研究主要集中在基底型乳腺癌上。在这项研究中，我们研究了CCL 5缺失在管腔型乳腺癌的MMTV-PyMT转基因小鼠模型中的后果。在该模型中，CCL 5缺陷受试者的原发性肿瘤负荷和肺转移显著降低，发现该效应与Th 2（IL4_CD4_T）细胞缺陷相关。机制研究表明，CCL 5激活CCR 3，一种在CD4_T细胞上高度表达的趋化因子受体，并且还增强Gfi 1表达以促进Th 2细胞的分化，这增强了肿瘤相关骨髓细胞的促转移活性。临床上，这种免疫抑制性Th 2表型的极化在晚期管腔型乳腺癌患者中也很明显。因此，我们的研究结果表明，CCL 5/CCR 3信号通过诱导CD4_T细胞的Th 2极化促进转移，这对管腔型乳腺癌的预后和免疫治疗有意义。(C)2015年AACR。
The tumor-promoting chemokine CCL5 has been implicated in malignant transformation of breast epithelial cells, with studies to date focusing mainly on basal-type breast cancers. In this study, we investigated the consequences of CCL5 deletion in the MMTV-PyMT transgenic mouse model of luminal breast cancer. In this model, primary tumor burden and pulmonary metastases were reduced significantly in CCL5-deficient subjects, an effect found to be associated with a deficit of Th2 (IL4_CD4_T) cells. Mechanistic investigations revealed that CCL5 activates CCR3, a highly expressed chemokine receptor on CD4_T cells, and also boosts Gfi1 expression to promote the differentiation of Th2 cells, which enhance the prometastatic activity of tumor-associated myeloid cells. Clinically, polarization toward this immunosuppressive Th2 phenotype was also evident in patients with advanced luminal breast cancer. Thus, our findings showed that CCL5/CCR3 signaling promotes metastasis by inducing Th2 polarization of CD4_T cells, with implications for prognosis and immunotherapy of luminal breast cancer. (C) 2015 AACR.