Immunotherapeutics Section, Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, MD 21224, USA.
J Immunother. 2013 May;36(4):258-67. doi: 10.1097/CJI.0b013e318294357c.
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.
尽管反义寡核苷酸/RNAi 技术具有很大的吸引力，但由于缺乏靶向递送至体内原代免疫细胞并转导的方法，其临床应用受到了限制。在这里，我们设计了一种基于趋化因子 CCL17 的策略（TARC-arp），通过其趋化因子受体将抑制性寡核苷酸递送至免疫细胞中，从而瞬时沉默基因的表达。在使用已建立的 4T1.2 乳腺癌的小鼠进行的建模研究中，我们表明 CCR4 细胞（特别是 FoxP3 调节性 T 细胞（Treg））产生的 IL10 在肺转移中起着重要作用。因此，TARC-arp 介导的 CCR4 Treg 中 IL10 或 FoxP3 的沉默足以阻止肺转移。因此，我们提供了一种简单的解决方案，规避了 RNAi 在体内使用的问题，表明通过将抑制性寡核苷酸与趋化因子一起递送至选择性免疫细胞亚群来灭活，可成功控制疾病结局。
