Inhibition of Lung Metastasis by Chemokine CCL17-mediated In Vivo Silencing of Genes in CCR4+ Tregs

被引:18
作者
Biragyn, Arya [1 ]
Bodogai, Monica [1 ]
Olkhanud, Purevdorj B. [1 ]
Denny-Brown, Sinan R. [1 ]
Puri, Nitin [2 ]
Ayukawa, Koichi [3 ]
Kanegasaki, Shiro [3 ]
Hogaboam, Cory M. [4 ]
Wejksza, Katarzyna [1 ]
Lee-Chang, Catalina [1 ]
机构
[1] NIA, Immunotherapeut Sect, Lab Mol Biol & Immunol, Baltimore, MD 21224 USA
[2] Life Technol, Amb Prod, Austin, TX USA
[3] Effector Cell Inst Inc, Kawasaki, Kanagawa, Japan
[4] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI USA
关键词
chemokine; Tregs; metastasis; siRNA delivery; IL10; FoxP3; REGULATORY T-CELLS; BREAST-CANCER METASTASIS; PERIPHERAL-BLOOD; SUPPRESSOR-CELLS; CUTTING EDGE; BONE-MARROW; INFLAMMATION; EXPRESSION; RECEPTORS; EFFECTOR;
D O I
10.1097/CJI.0b013e318294357c
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Despite significant attractiveness of antisense oligonucleotide/RNAi technology, its clinical application has been precluded by a lack of methods for targeted delivery and transduction of primary immune cells in vivo. Here, we devised a chemokine CCL17-based strategy (TARC-arp) that transiently silences expression of genes in immune cells by delivering inhibitory oligonucleotides through their chemokine receptors. In modeling studies using mice with established 4T1.2 breast cancer, we show that IL10 produced by CCR4(+) cells, in particular FoxP3(+) regulatory T cells (Tregs), plays an important role in lung metastasis. As such, TARC-arp-mediated silencing of IL10 or FoxP3 in CCR4(+) Tregs is sufficient to block lung metastasis. Thus, we provide a simple solution that circumvents the problems of RNAi use in vivo, indicating that a disease outcome can be successfully controlled by delivering inhibitory oligonucleotides with chemokines to inactivate a selective subset of immune cells.
引用
收藏
页码:258 / 267
页数:10
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