Anti-tumor immune responses of tumor-associated macrophages via toll-like receptor 4 triggered by cationic polymers
Anti-tumor immune responses of tumor-associated macrophages via toll-like receptor 4 triggered by cationic polymers
复制标题
阳离子聚合物通过 Toll 样受体 4 触发肿瘤相关巨噬细胞的抗肿瘤免疫反应。
DOI：
10.1016/j.biomaterials.2012.09.062
复制
发表时间：
2013-01-01
期刊：
影响因子：
14
通讯作者：
Zhang, Junfeng
中科院分区：
文献类型：
--
作者：
Huang, Zhen;Yang, Yang;Zhang, Junfeng
Toll样受体（TLR）激动剂是肿瘤免疫治疗的潜在治疗试剂。具有核酸药物递送能力的阳离子聚合物如聚乙烯亚胺（PEI）被批准用于临床试验，并且最近的报道表明这些阳离子聚合物具有由TLR介导的显著免疫活性。在本研究中，我们证明了阳离子聚合物，如PEI和阳离子葡聚糖可以逆转肿瘤相关巨噬细胞（TAMs）的极化，并促进IL-12的表达在体外和体内。阳离子聚合物的刺激作用在用TLR-4阻断抗体预处理的TAM或来自TLR-4敲除小鼠的TAM中显著减弱。此外，这些阳离子聚合物通过促进Th 1和NK细胞浸润、抑制肿瘤血管生成和延长携带肉瘤的野生型的存活而发挥直接的杀肿瘤活性。这些现象在TLR-4基因敲除小鼠中被消除，表明免疫刺激主要由TLR-4介导。总之，这些结果表明，阳离子聚合物可以通过TLR-4信号转导转化TAM的免疫耐受表型，从而促进治疗性抗肿瘤免疫。我们目前的研究表明，一类新的药物可作为未来癌症免疫治疗的候选药物。C）2012 Elsevier Ltd.保留所有权利。
Agonists of toll-like receptors (TLRs) are potential therapeutic reagents for cancer immunotherapy. Cationic polymers such as polyethyleneimine (PEI) with nucleic acid drug delivery capability are approved for use in clinical trials, and recent reports indicate that these cationic polymers have significant immunological activity mediated by TLRs. In the present study, we demonstrated that cationic polymers such as PEI and cationic dextran could reverse tumor-associated macrophages (TAMs) polarization and promote IL-12 expression both in vitro and in vivo. The stimulatory role of cationic polymers was remarkably attenuated in TAMs pre-treated with TLR-4 blocking antibody or TAMs from TLR-4 knockout mice. Additionally, these cationic polymers exerted direct tumoricidal activity by promoting Th 1 and NK cell infiltration, suppressing tumor angiogenesis and prolonging the survival of sarcoma-bearing wild-type. These phenomena were abrogated in TLR-4 knockout mice, suggesting that the immune stimulation was primarily mediated by TLR-4. In conclusion, these results demonstrated that cationic polymers could transform the immunotolerogenic phenotype of TAMs through TLR-4 signaling, thereby promoting therapeutic anti-tumor immunity. Our present study suggests a new class of drugs as a candidate for future cancer immunotherapy. C) 2012 Elsevier Ltd. All rights reserved.