A new cancer immunotherapy via simultaneous DC-mobilization and DC-targeted IDO gene silencing using an immune-stimulatory nanosystem
A new cancer immunotherapy via simultaneous DC-mobilization and DC-targeted IDO gene silencing using an immune-stimulatory nanosystem
复制标题
使用免疫刺激纳米系统同时进行 DC 动员和 DC 靶向 IDO 基因沉默的新型癌症免疫疗法
DOI：
10.1002/ijc.31588
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发表时间：
2018
影响因子：
6.4
通讯作者：
Min Weiping
中科院分区：
文献类型：
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作者：
Zhang Yujuan;Fu Jiamin;Shi Yanmei;Peng Shanshan;Cai Ying;Zhan Xuelin;Song Na;Liu Yanling;Wang Zhigang;Yu Yanrong;Wang Yifan;Shi Qiaofa;Fu Yingyuan;Yuan Keng;Zhou Nanjin;Joshi Rakesh;Ichim Thomas E;Min Weiping
负性免疫调节分子的活性，如吲哚胺2,3加氧酶（IDO），显著减弱DC（树突状细胞）介导的免疫治疗。我们之前报道过使用siRNA敲除IDO可以重新获得抗肿瘤免疫。然而，用于体内动员DC的DC靶向siRNA递送系统仍有待开发，而用于癌症免疫治疗的动员DC的基因沉默从未被探索过。在我们的研究中，我们开发了一种新的DC靶向siRNA递送系统，man - GNR - siIDO，作为IDO特异性siRNA的纳米载体（siIDO）和甘露糖（man）作为靶向DC的引导分子。我们在Flt3 - L（一种受体型酪氨酸激酶配体）动员的dc中探索了免疫刺激man - GNR - siIDO纳米结构，用于肺癌免疫治疗。体内DC靶向基因沉默IDO可促进DC成熟、上调肿瘤抗原特异性T细胞增殖和增强肿瘤特异性细胞毒性，从而产生强大的抗肿瘤免疫。man - GNR - siIDO和Flt3 - L联合治疗Lewis肺癌（LLC）小鼠，可显著抑制肿瘤生长，延缓肿瘤形成，表明man - GNR - siIDO系统在Flt3 - L动员dc中治疗肺癌免疫治疗的可行性。因此，我们的研究强调了通过man - GNR - siIDO和Flt3 - L治疗同时激活DC -动员和DC -靶向IDO基因沉默的一流抗癌免疫疗法的临床潜力。
The activity of negative immune regulatory molecules, such as indoleamine 2,3‐oxygenase (IDO), significantly attenuates DC (Dendritic cells)‐mediated immunotherapy. We have previously reported that knockdown of IDO using siRNA can reinstall anti‐tumor immunity. However, a DC‐targeted siRNA delivery system for in vivo mobilized DCs remains to be developed, while gene silencing in mobilized DCs for cancer immunotherapy has never been explored. In our study, we developed a novel DC‐targeted siRNA delivery system, man‐GNR‐siIDO, using as a nanocarrier of siRNA specific for IDO (siIDO) and mannose (man) as a guide molecule for targeting DCs. We explored the immunostimulatory man‐GNR‐siIDO nano‐construct in DCs mobilized by Flt3‐L, a receptor‐type tyrosine kinase ligand, for lung cancer immunotherapy. In vivo DC‐targeted gene silencing of IDO resulted in robust anti‐tumor immunity as evidenced by promoting DC maturation, up‐regulating tumor antigen‐specific T‐cell proliferation and enhancing tumor‐specific cytotoxicity. A combinatorial treatment for Lewis Lung Carcinoma (LLC)‐bearing mice, with man‐GNR‐siIDO and Flt3‐L, significantly attenuated tumor growth and delayed tumor formation, suggesting the treatment feasibility of the man‐GNR‐siIDO system in Flt3‐L mobilized DCs in the immunotherapy of lung cancer. Therefore, our study highlights a clinical potential for a first‐in‐class anti‐cancer immunotherapy through simultaneous DC‐mobilization and DC‐targeted gene silencing of IDO with man‐GNR‐siIDO and Flt3‐L treatments.