Tumor-Derived Chemokine CCL5 Enhances TGF-β-Mediated Killing of CD8+ T Cells in Colon Cancer by T-Regulatory Cells
Tumor-Derived Chemokine CCL5 Enhances TGF-β-Mediated Killing of CD8+ T Cells in Colon Cancer by T-Regulatory Cells
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DOI：
10.1158/0008-5472.can-11-2493
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发表时间：
2012-03-01
期刊：
影响因子：
11.2
通讯作者：
Lin, Chun-Yen
中科院分区：
文献类型：
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作者：
Chang, Li-Yuan;Lin, Yung-Chang;Lin, Chun-Yen
趋化因子CCL 5/RANTES在癌症中高度表达，其有助于炎症和恶性进展。在这项研究中，我们发现CCL 5在结直肠癌的免疫逃逸中起着关键作用。我们发现，人类和小鼠结肠肿瘤细胞中CCL 5的高水平表达与CD 8（+）T细胞的高水平凋亡和T调节细胞（T-reg）的浸润相关。在小鼠细胞中，RNA干扰（RNAi）介导的CCL 5敲低延迟了免疫活性同源宿主中的肿瘤生长，但对免疫缺陷宿主中的肿瘤生长没有影响。肿瘤生长减少与肿瘤中T-reg浸润和CD 8（+）T细胞凋亡减少相关。值得注意的是，我们发现CCL 5增强了T-reg对CD 8（+）T细胞的细胞毒性。我们还发现，在缺乏CCR 5，aCCL 5受体的小鼠中，肿瘤生长减少，其中Treg细胞浸润和CD 8（+）T细胞凋亡也出现了类似的减少。TGF-β信号阻断减少了CD 8（+）T细胞的凋亡，暗示TGF-β是CCL 5作用的效应物。支持这一观点的是，CCL 5不能增强CCR 5缺陷型T-reg产生TGF-β的能力，也不能增强它们对CD 8（+）T细胞的细胞毒性作用。CCR 5信号传导阻断也以与CCL 5信号传导阻断相同的方式降低了T-reg抑制CD 8（+）T细胞的抗肿瘤应答的体内抑制能力。总之，我们的研究结果确定了CCL 5/CCR 5信号转导将Treg招募到肿瘤中，并增强了它们杀死抗肿瘤CD 8（+）T细胞的能力，从而定义了结直肠癌免疫逃逸的新机制。Cancer Res; 72（5）; 1092-102. (C)2012年AACR。
Chemokine CCL5/RANTES is highly expressed in cancer where it contributes to inflammation and malignant progression. In this study, we show that CCL5 plays a critical role in immune escape in colorectal cancer. We found that higher levels of CCL5 expression in human and murine colon tumor cells correlated with higher levels of apoptosis of CD8(+) T cells and infiltration of T-regulatory cells (T-reg). In mouse cells, RNA interference (RNAi)-mediated knockdown of CCL5 delayed tumor growth in immunocompetent syngeneic hosts but had no effect on tumor growth in immunodeficient hosts. Reduced tumor growth was correlated with a reduction in T-reg infiltration and CD8(+) T-cell apoptosis in tumors. Notably, we found that CCL5 enhanced the cytotoxicity of T-reg against CD8(+) T cells. We also found tumor growth to be diminished in mice lacking CCR5, aCCL5 receptor, where a similar decrease in both Treg cell infiltration and CD8(+) T-cell apoptosis was noted. TGF-beta signaling blockade diminished apoptosis of CD8(+) T cells, implicating TGF-beta as an effector of CCL5 action. In support of this concept, CCL5 failed to enhance the production of TGF-b by CCR5-deficient T-reg or to enhance their cytotoxic effects against CD8(+) T cells. CCR5 signaling blockade also diminished the in vivo suppressive capacity of T-reg in inhibiting the antitumor responses of CD8(+) T cells, in the same way as CCL5 signaling blockade. Together, our findings establish that CCL5/CCR5 signaling recruits Treg to tumors and enhances their ability to kill antitumor CD8(+) T cells, thereby defining a novel mechanism of immune escape in colorectal cancer. Cancer Res; 72(5); 1092-102. (C) 2012 AACR.