组蛋白去乙酰化酶抑制剂联合HPV16E7-DNA疫苗治疗宫颈癌的效果及机制研究  

Effect of histone deacetylase inhibitor combined with HPV16E7-DNA vaccine in the treatment of cervical cancer and study on its mechanism

作　　者：黄卓敏[1] 李晴 姚秀华[1] 金平[1] 

机构地区：[1]南方医科大学深圳市妇幼保健院妇科,广东深圳518028

出　　处：《中国医药导报》2018年第5期18-21,共4页China Medical Herald

基　　金：广东省深圳市科技创新委员会基础研究项目(JCYJ20150402090413004)

摘　　要：目的探讨组蛋白去乙酰化酶抑制剂(HDACI)伏立诺他(SAHA)联合人乳头瘤病毒16 E7-DNA(HPV16E7-DNA)疫苗治疗宫颈癌的效果及免疫机制。方法建立TC-1宫颈癌小鼠模型,负瘤第5天,采用随机数字表法将小鼠分为HPV16E7-DNA组、SAHA组、SAHA联合HPV16E7-DNA组、对照组,用药方案:HPV16E7-DNA组给予疫苗5μg/kg,SAHA组给予SAHA 20 mg/kg,SAHA联合HPV16E7-DNA组给予疫苗5μg/kg+SAHA 20 mg/kg,对照组给予100μL磷酸盐溶液(PBS)。每3天1次,共4次。绘制肿瘤生长曲线;流式细胞仪检测各组小鼠外周血CD8^+T细胞的数量;体外实验检测不同剂量SAHA(25.0、12.5 nmol/L)对TC-1细胞MHCⅠ类分子H-2K^b表达的影响。结果与其他三组比较,SAHA联合HPV16E7-DNA组的肿瘤生长速度明显减慢,小鼠外周血HPV16E7特异性CD8^+T细胞的数量增高(P<0.05)。体外实验结果提示,与对照组比较,SAHA组细胞MHCⅠ类分子H-2K^b的表达明显增高(P<0.05),低剂量与高剂量SAHA组之间比较差异无统计学意义(P>0.05)。结论 HDACI联合HPV16E7-DNA疫苗可能通过上调肿瘤细胞MHCⅠ类分子的表达,激活机体CD8^+T细胞免疫反应,从而产生明显的抗肿瘤效应,有望用于宫颈癌的免疫治疗。Objective To investigate the effect of combination of histone deacetylase inhibitor （HDACI） Suberoylanilide Hydroxamic Acid （SAHA） combined with human papilloma virus 16 E7-DNA （HPV16ET-DNA） vaccine in the treatment of cervical cancer and its immunological mechanism. Methods The model of mice with TC-1 cervical cancer was made, then on the 5th day after tumor bearing, the mice were randomly divided into HPV16ET-DNA group, SAHA group, SAHA and HPV16E7-DNA group, control group by random number table method. The therapeutic regimen was as followed： HPV16E7-DNA group was given vaccine 5 μg/kg, SAHA group was given SAHA 20 mg/kg, SAHA and HPV16E7-DNA group was given vaccine 5 μg/kg＋SAHA 20 mg/kg, the control group was given 100 μL phosphate solutions （PBS）. Once every 3 days, total for 4 times. The tumor growth curve was drawn; the amount of CD8^＋T ceils in peripheral blood of mice in each group was detected by flow cytometry; the effects of different doses of SAHA （25.0, 12.5 nmol/L） for the expression of H-2K^b of MHC class Ⅰ in TC-1 cells were detected by experiment in vitro. Results Compared with the other three groups, the tumor growth rate in SAHA and HPV16E7-DNA group was significantly slowed down, the amount of HPVE7 specific CD8^＋T cells in peripheral blood of mice was significantly increased （P 〈 0.05）. In-vitro experiment showed that compared with control group, the expression of H-2K^b of MHC class Ⅰ in SAHA group was increased significantly （P 〈 0.05）, while there was no significant difference between low dose of SAHA group and high dose of SAHA group （P 〉 0.05）. Conclusion HDACI combined with HPV16E7-DNA vaccine comes into significant anti-tumor effects may be through uo-regulating expression of MHC class Ⅰ of the tumor cells and aetivating the immune response of CD8^＋T cells, which is expected to be used in the immunotherapy of cervical cancer.

关 键 词：组蛋白去乙酰化酶抑制剂 HPV16-E7疫苗 宫颈癌 CD8^+T细胸 MHCⅠ类分子 

分 类 号：R737.33[医药卫生—肿瘤]