癌症研究
生物
白血病
免疫学
TLR9型
免疫系统
DNA甲基化
生物化学
基因
基因表达
作者
Dewan Md Sakib Hossain,Cédric Dos Santos,Qifang Zhang,Anna Kozłowska,Hongjun Liu,Chan Gao,Dayson Moreira,Piotr Swiderski,Agnieszka Jóźwiak,Justin Kline,Stephen J. Forman,Ravi Bhatia,Ya Huei Kuo,Marcin Kortylewski
出处
期刊:Blood
[American Society of Hematology]
日期:2014-01-02
卷期号:123 (1): 15-25
被引量:80
标识
DOI:10.1182/blood-2013-07-517987
摘要
Signal transducer and activator of transcription 3 (STAT3) is an oncogene and immune checkpoint commonly activated in cancer cells and in tumor-associated immune cells. We previously developed an immunostimulatory strategy based on targeted Stat3 silencing in Toll-like receptor 9 (TLR9)-positive hematopoietic cells using CpG-small interfering RNA (siRNA) conjugates. Here, we assessed the therapeutic effect of systemic STAT3 blocking/TLR9 triggering in disseminated acute myeloid leukemia (AML). We used mouse Cbfb-MYH11/Mpl-induced leukemia model, which mimics human inv(16) AML. Our results demonstrate that intravenously delivered CpG-Stat3 siRNA, but not control oligonucleotides, can eradicate established AML and impair leukemia-initiating potential. These antitumor effects require host's effector T cells but not TLR9-positive antigen-presenting cells. Instead, CpG-Stat3 siRNA has direct immunogenic effect on AML cells in vivo upregulating major histocompatibility complex class-II, costimulatory and proinflammatory mediators, such as interleukin-12, while downregulating coinhibitory PD-L1 molecule. Systemic injections of CpG-Stat3 siRNA generate potent tumor antigen-specific immune responses, increase the ratio of tumor-infiltrating CD8(+) T cells to regulatory T cells in various organs, and result in CD8(+) T-cell-dependent regression of leukemia. Our findings underscore the potential of using targeted STAT3 inhibition/TLR9 triggering to break tumor tolerance and induce immunity against AML and potentially other TLR9-positive blood cancers.
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