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肿瘤源趋化因子 CCL5 通过调节性 T 细胞增强 TGF-β 介导的结肠癌中 CD8(+) T 细胞的杀伤作用。

Tumor-derived chemokine CCL5 enhances TGF-β-mediated killing of CD8(+) T cells in colon cancer by T-regulatory cells.

机构信息

Graduate Institute of Biomedical Sciences, Chang Gung University, Taiwan.

出版信息

Cancer Res. 2012 Mar 1;72(5):1092-102. doi: 10.1158/0008-5472.CAN-11-2493. Epub 2012 Jan 26.

Abstract

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, a CCL5 receptor, where a similar decrease in both T(reg) cell infiltration and CD8(+) T-cell apoptosis was noted. TGF-β signaling blockade diminished apoptosis of CD8(+) T cells, implicating TGF-β as an effector of CCL5 action. In support of this concept, CCL5 failed to enhance the production of TGF-β 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 T(reg) to tumors and enhances their ability to kill antitumor CD8(+) T cells, thereby defining a novel mechanism of immune escape in colorectal cancer.

摘要

趋化因子 CCL5/RANTES 在癌症中高度表达,促进炎症和恶性进展。在这项研究中,我们表明 CCL5 在结直肠癌的免疫逃避中起关键作用。我们发现,人源和鼠源结肠肿瘤细胞中 CCL5 表达水平越高,CD8+T 细胞的凋亡水平和 T 调节细胞(Treg)的浸润水平越高。在鼠源细胞中,RNA 干扰(RNAi)介导的 CCL5 敲低延迟了免疫活性同基因宿主中的肿瘤生长,但对免疫缺陷宿主中的肿瘤生长没有影响。肿瘤生长的减少与肿瘤中 Treg 浸润和 CD8+T 细胞凋亡的减少相关。值得注意的是,我们发现 CCL5 增强了 Treg 对 CD8+T 细胞的细胞毒性。我们还发现,缺乏 CCL5 受体 CCR5 的小鼠肿瘤生长减少,同时观察到 Treg 细胞浸润和 CD8+T 细胞凋亡的相似减少。TGF-β信号通路阻断减少了 CD8+T 细胞的凋亡,表明 TGF-β是 CCL5 作用的效应因子。为了支持这一概念,CCL5 未能增强 CCR5 缺陷型 Treg 产生 TGF-β的能力,也未能增强其对 CD8+T 细胞的细胞毒性作用。CCR5 信号通路阻断也减弱了 Treg 在体内抑制 CD8+T 细胞抗肿瘤反应的抑制能力,与 CCL5 信号通路阻断的方式相同。总之,我们的研究结果表明,CCL5/CCR5 信号通路招募 Treg 进入肿瘤,并增强其杀死抗肿瘤 CD8+T 细胞的能力,从而确定了结直肠癌免疫逃避的一种新机制。

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