TLR9-mediated siRNA delivery for targeting of normal and malignant human hematopoietic cells in vivo
TLR9-mediated siRNA delivery for targeting of normal and malignant human hematopoietic cells in vivo
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DOI：
10.1182/blood-2012-07-442590
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发表时间：
2013-02-21
期刊：
影响因子：
20.3
通讯作者：
Kortylewski, Marcin
中科院分区：
文献类型：
--
作者：
Zhang, Qifang;Hossain, Dewan Md Sakib;Kortylewski, Marcin
STAT3在癌细胞和肿瘤相关免疫细胞中起作用，以促进癌症进展。作为一种转录因子，它是一个非常理想但难以药理学抑制的靶点。我们最近已经表明，TLR9激动剂CpG寡核苷酸可用于靶向siRNA递送至小鼠免疫细胞。在本研究中，我们证明了一个类似的策略，允许在正常和恶性人类TLR9（+）造血细胞在体内靶向基因沉默。我们已经开发了新的人细胞特异性CpG（A）-STAT 3 siRNA缀合物，其能够在体外诱导TLR9依赖性基因沉默和原代免疫细胞（如髓样树突细胞、浆细胞样树突细胞和B细胞）的活化。TLR9也由几种人类恶性血液病表达，包括B细胞淋巴瘤、多发性骨髓瘤和急性髓性白血病。我们进一步证明了致癌蛋白如STAT3或BCL-X-L在体内被TLR9（+）血液肿瘤细胞中的特异性CpG（A）-siRNA有效地敲低。使用CpG（A）-siRNA靶向生存信号抑制几种异种移植多发性骨髓瘤和急性髓性白血病肿瘤的生长。CpG（A）-STAT 3 siRNA在体外对正常人白细胞具有免疫刺激作用且无毒。本研究的结果显示了使用杀肿瘤/免疫刺激性CpG-siRNA寡核苷酸作为血液恶性肿瘤的新型双管齐下的治疗策略的潜力。
STAT3 operates in both cancer cells and tumor-associated immune cells to promote cancer progression. As a transcription factor, it is a highly desirable but difficult target for pharmacologic inhibition. We have recently shown that the TLR9 agonists CpG oligonucleotides can be used for targeted siRNA delivery to mouse immune cells. In the present study, we demonstrate that a similar strategy allows for targeted gene silencing in both normal and malignant human TLR9(+) hematopoietic cells in vivo. We have developed new human cell-specific CpG(A)-STAT3 siRNA conjugates capable of inducing TLR9-dependent gene silencing and activation of primary immune cells such as myeloid dendritic cells, plasmacytoid dendritic cells, and B cells in vitro. TLR9 is also expressed by several human hematologic malignancies, including B-cell lymphoma, multiple myeloma, and acute myeloid leukemia. We further demonstrate that oncogenic proteins such as STAT3 or BCL-X-L are effectively knocked down by specific CpG(A)-siRNAs in TLR9(+) hematologic tumor cells in vivo. Targeting survival signaling using CpG(A)-siRNAs inhibits the growth of several xenotransplanted multiple myeloma and acute myeloid leukemia tumors. CpG(A)-STAT3 siRNA is immunostimulatory and nontoxic for normal human leukocytes in vitro. The results of the present study show the potential of using tumoricidal/immunostimulatory CpG-siRNA oligonucleotides as a novel 2-pronged therapeutic strategy for hematologic malignancies.