Reprogramming tumor-associated dendritic cells in vivo using miRNA mimetics triggers protective immunity against ovarian cancer.
Reprogramming tumor-associated dendritic cells in vivo using miRNA mimetics triggers protective immunity against ovarian cancer.
复制标题
使用miRNA Mimetics在体内重新编程与肿瘤相关的树突状细胞触发了针对卵巢癌的保护性免疫。
DOI：
10.1158/0008-5472.can-11-3160
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发表时间：
2012-04-01
期刊：
影响因子：
11.2
通讯作者：
Conejo-Garcia JR
中科院分区：
文献类型：
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作者：
Cubillos-Ruiz JR;Baird JR;Tesone AJ;Rutkowski MR;Scarlett UK;Camposeco-Jacobs AL;Anadon-Arnillas J;Harwood NM;Korc M;Fiering SN;Sempere LF;Conejo-Garcia JR
调节microRNA（miRNAs）的活性为新型癌症干预提供了机会。然而，低生物利用度和差的细胞摄取是将miRNA模拟物特异性递送至肿瘤细胞的主要挑战。在这里，我们利用卵巢癌相关树突状细胞（DC）自发增强的内吞活性来选择性地补充免疫刺激性miRNA miR-155。携带模拟内源性pre-miRNA（而不是siRNA样寡核苷酸）的凸起结构的寡核苷酸双链体的纳米颗粒的体内处理显著增强了miR-155活性，而没有使RISC饱和。合成miR-155的内源性加工有利于Ago 2加载，并且在较小程度上有利于Ago 4加载，导致全基因组转录变化，包括多种免疫抑制介质的沉默。相应地，肿瘤浸润性DC从免疫抑制性转化为高度免疫刺激性细胞，能够触发有效的抗肿瘤反应，消除已建立的卵巢癌的进展。我们的研究结果证明了使用非病毒方法在体内补充/补充miRNAs以增强针对致死性肿瘤的保护性免疫的可行性和治疗潜力。因此，我们提供了一个平台，一个优化的设计和非病毒的miRNA模拟物的临床试验的机制原理。
Modulating the activity of microRNAs (miRNAs) provides opportunities for novel cancer interventions. However, low bioavailability and poor cellular uptake are major challenges for delivering miRNA mimetics specifically to tumor cells. Here, we took advantage of the spontaneous enhanced endocytic activity of ovarian cancer-associated dendritic cells (DCs) to selectively supplement the immunomostimulatory miRNA miR-155. In vivo processing of nanoparticles carrying oligonucleotide duplexes mimicking the bulged structure of endogenous pre-miRNA (but not siRNA-like oligonucleotides) dramatically augmented miR-155 activity without saturating the RISC. Endogenous processing of synthetic miR-155 favored Ago2- and, to a lesser extent, Ago4-loading, resulting in genome-wide transcriptional changes that included silencing of multiple immunosuppressive mediators. Correspondingly, tumor-infiltrating DCs were transformed from immunosuppressive to highly immunostimulatory cells capable of triggering potent anti-tumor responses that abrogated the progression of established ovarian cancers. Our results demonstrate both the feasibility and therapeutic potential of supplementing/replenishing miRNAs in vivo using non-viral approaches to boost protective immunity against lethal tumors. Thus, we provide a platform, an optimized design and a mechanistic rationale for the clinical testing of non-viral miRNA mimetics.