Brown Lloyd, Roda Julie, Terrell Catherine, Chaudhury Abhik Ray, Crespin Tim, Carson William E, Lesinski Gregory B
Department of Surgery, Human Cancer Genetics Program, Columbus, OH, USA.
Surgery. 2006 Aug;140(2):297-306. doi: 10.1016/j.surg.2006.05.005.
We hypothesized that interferon alpha (IFN-alpha) and unmethylated cytosine-phosphothioate-guanine (CpG)-rich oligodexoynucleotides (CpG ODNs) would elicit potent antitumor activity due to the ability of this treatment combination to activate complimentary signal transduction intermediates.
Peripheral blood mononuclear cells treated with CpG ODNs, IFN-alpha, or both agents combined were evaluated for cytotoxicity against human melanoma cells, Jak-STAT signal transduction by flow cytometry, and ISG-15 gene expression by real-time polymerase chain reaction. The effects of CpG ODNs and IFN-alpha were evaluated in murine models of melanoma in wild-type, IFN-gamma-deficient, and STAT1-deficient mice. Negative controls in all experiments included treatment with control ODN or phosphate-buffered saline.
Treatment of peripheral blood mononuclear cells with a combination of CpG ODNs and IFN-alpha resulted in enhanced cytotoxicity, activation of natural killer cells, IFN-alpha-induced STAT1 phosphorylation, and transcription levels of ISG-15. These immunostimulatory effects of CpG ODNs were associated with increased expression of STAT1 and STAT2 proteins. Administration of CpG ODNs plus IFN-alpha elicited superior antitumor activity in a murine model of B16 melanoma compared with either agent alone. The antitumor properties of CpG ODNs were dependent on STAT1-mediated signal transduction within the host but independent of endogenously produced IFN-gamma.
CpG ODNs represent potent immune stimulants that elicit antitumor effects through STAT1-mediated signal transduction.
我们假设，由于这种联合治疗能够激活互补的信号转导中间体，干扰素α（IFN-α）和富含未甲基化胞嘧啶-磷酸硫代-鸟嘌呤（CpG）的寡脱氧核苷酸（CpG ODNs）将引发强大的抗肿瘤活性。
对用CpG ODNs、IFN-α或两种药物联合处理的外周血单个核细胞进行评估，检测其对人黑色素瘤细胞的细胞毒性、通过流式细胞术检测Jak-STAT信号转导以及通过实时聚合酶链反应检测ISG-15基因表达。在野生型、IFN-γ缺陷型和STAT1缺陷型小鼠的黑色素瘤小鼠模型中评估CpG ODNs和IFN-α的作用。所有实验中的阴性对照包括用对照ODN或磷酸盐缓冲盐水处理。
用CpG ODNs和IFN-α联合处理外周血单个核细胞导致细胞毒性增强、自然杀伤细胞激活、IFN-α诱导的STAT1磷酸化以及ISG-15的转录水平升高。CpG ODNs的这些免疫刺激作用与STAT1和STAT2蛋白表达增加有关。与单独使用任何一种药物相比，在B16黑色素瘤小鼠模型中，给予CpG ODNs加IFN-α可引发更强的抗肿瘤活性。CpG ODNs的抗肿瘤特性依赖于宿主内STAT1介导的信号转导，但与内源性产生的IFN-γ无关。
CpG ODNs是强大的免疫刺激剂，可通过STAT1介导的信号转导引发抗肿瘤作用。
