Both treated and untreated tumors are eliminated by short hairpin RNA-based induction of target-specific immune responses
Both treated and untreated tumors are eliminated by short hairpin RNA-based induction of target-specific immune responses
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DOI：
10.1073/pnas.0812085106
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发表时间：
2009-05-19
影响因子：
11.1
通讯作者：
McMillan, Nigel A. J.
中科院分区：
文献类型：
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作者：
Gu, Wenyi;Cochrane, Melanie;McMillan, Nigel A. J.
用于癌症治疗的RNA干扰(RNAi)依赖于通过下调靶基因来直接杀死癌细胞的能力，但传递和疗效问题限制了临床应用。此外，目前使用免疫缺陷动物模型的研究忽略了与适应性免疫系统的潜在相互作用。以前已经观察到，由于病毒产生有缺陷的核糖体产物，某些病毒抗原似乎比正常蛋白更快地被呈递到免疫系统。鉴于RNAi可能导致截短的mRNAs的产生，我们想知道是否有可能有类似的目标基因的免疫呈递机制。在这里，我们证明了RNAi裂解的mRNAs可以被翻译成不完整的蛋白质，如果裂解位于细胞毒性T细胞表位的下游，则会导致靶蛋白的呈递增加和肿瘤保护性免疫反应的产生。我们表明，接种了经这种短发夹状RNA(ShRNAs)处理的肿瘤细胞的小鼠可以免受随后未经治疗的肿瘤的攻击。然而，只有当shRNAs靶向优势细胞毒性T细胞(CTL)表位下游时，才能发现保护作用。我们的工作表明，RNAi可以改变对靶点的免疫，并表明并不是所有的肿瘤细胞都需要直接接触RNAi才能在体内有效治疗，这为一种新的基于RNAi的治疗指明了方向。
RNA interference (RNAi) for cancer treatment relies on the ability to directly kill cancer cells via down-regulation of target genes, but issues of delivery and efficacy have limited clinical adoption. Furthermore, current studies using immune-deficient animal models disregard potential interactions with the adaptive immune system. It has previously been observed that certain viral antigens appear to be more rapidly presented to the immune system than normal proteins due to the production of defective ribosomal products by the virus. Given that RNAi could potentially result in the generation of truncated mRNAs, we wondered whether a similar mechanism of immune presentation of a target gene was possible. Here we show that RNAi-cleaved mRNAs can be translated into incomplete protein, and if cleavage was downstream of cytotoxic T cell epitopes, resulted in increased presentation of target protein and the generation of a tumor-protective immune response. We show that mice inoculated with tumor cells treated with such short hairpin RNAs (shRNAs) were protected from subsequent challenge with untreated tumors. However, protection was only found if shRNAs were targeted downstream of the dominant cytotoxic T cell (CTL) epitope. Our work suggests that RNAi can alter immunity to targets and shows that not all tumor cells require direct RNAi exposure for treatment to be effective in vivo, pointing the way to a new class of RNAi-based therapy.