IL-15/sIL-15Rα gene transfer suppresses Lewis lung cancer growth in the lungs, liver and kidneys.
IL-15/sIL-15Rα gene transfer suppresses Lewis lung cancer growth in the lungs, liver and kidneys.
复制标题
IL-15/sIL-15Rα 基因转移抑制路易斯肺癌在肺、肝和肾中的生长。
DOI：
10.1038/cgt.2015.67
复制
发表时间：
2016
影响因子：
6.4
通讯作者：
Liu,D
中科院分区：
文献类型：
--
作者：
Sun,H;Liu,D
近40%的肺癌患者在诊断时在其他器官有肿瘤生长。目前晚期肺癌患者的治疗策略主要是姑息性的，仅显示出适度的疗效。本研究利用流体动力学基因传递技术评价了白细胞介素(IL)-15/sIL-15Rα对肺、肝、肾生长的肺肿瘤的抗肿瘤活性。结果表明，尾静脉注射2 μg AG209 DP muIL-15sRα+ IL-15质粒，血清IL-15/sIL-15Rα在注射后1 d达到峰值~ 10 μg ml−1,3 d内逐渐下降至~ 5 ng ml−1。定量PCR分析显示，IL-15/sIL-15Rα的过表达诱导了自然杀伤细胞和T细胞的活化，其证据是肺、肝和肾中颗粒酶B、穿孔素、Ifn-γ、T-bet和Cd8等标记基因的mRNA水平升高。重要的是，单独转移Il-15/sIl-15Rα基因或联合吉西他滨化疗可显著抑制这三个器官的肿瘤生长，并将治疗小鼠的中位生存时间分别延长1.7倍和3.3倍。治疗的好处主要是阻断和消除肿瘤生长在肝脏和肾脏。综上所述，这些结果表明基于IL-15/ sil - 15r α的基因治疗可能是治疗晚期肺癌其他器官转移的有效途径。
Nearly 40% of people with lung cancer have tumor growth in other organs at the time of diagnosis. Current treatment strategies for patients with late-stage lung cancer are primarily palliative and only showed modest efficacy. The current study takes advantage of the hydrodynamic gene delivery technique to evaluate the antitumor activity of interleukin (IL)-15/sIL-15Rα on lung tumors growing in the lungs, liver and kidneys. We demonstrate that hydrodynamic tail vein injection of 2 μg of AG209 DP muIL-15sRα+ IL-15 plasmid resulted in serum IL-15/sIL-15Rα reaching a peak level of~ 10 μg ml− 1 1 day after the injection and gradually declined to~ 5 ng ml− 1 within 3 days. Quantitative PCR analysis revealed that overexpression of IL-15/sIL-15Rα induced the activation of natural killer and T cells, evidenced by increased mRNA levels of marker genes including granzyme B, perforin, Ifn-γ, T-bet and Cd8 in the lungs, liver and kidneys. Importantly, transfer of the Il-15/sIl-15Rα gene alone, or in combination with gemcitabine chemotherapy, significantly inhibited the tumor growth in these three organs and prolonged median survival time of treated mice by 1.7-and 3.3-fold, respectively. The therapeutic benefits are principally blockade and elimination of tumor growth in the liver and kidneys. Taken together, these results suggest that IL-15/sIL-15Rα-based gene therapy could be an effective approach to treat late-stage lung cancer with metastases in other organs.