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A new cancer immunotherapy via simultaneous DC‐mobilization and DC‐targeted IDO gene silencing using an immune‐stimulatory nanosystem
Author(s) -
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
Publication year - 2018
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.31588
Subject(s) - immunotherapy , gene silencing , cancer research , gene knockdown , immune system , cancer immunotherapy , dendritic cell , cancer , lewis lung carcinoma , medicine , immunology , biology , metastasis , cell culture , gene , biochemistry , genetics
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.