甲胎蛋白特异性肝癌疫苗体内杀伤肝癌细胞

Alpha fetal protein-specific hepatocellular carcinoma vaccines inhibit hepatocellular carcinoma growth in nude mice bearing human hepatocellular carcinoma

目的 探讨甲胎蛋白（AFP）肽片段或Lenti-AFP刺激的树突状细胞（DC）制备的肝癌疫苗用于肝癌免疫治疗的可行性.方法 采用慢病毒转染和AFP抗原决定簇肽制备的肝癌疫苗对4组荷瘤裸鼠（Lenti-AFP、AFP1、AFP542组及对照组）进行了体内肿瘤细胞杀伤实验,通过测定成瘤大小及相关细胞因子[白细胞介素（IL）-2和-10、干扰素-γ、肿瘤坏死因子-α、穿孔素、颗粒酶B、Fas配体]的变化,观察不同治疗组对裸鼠皮下成瘤及其恶化的影响.结果 AFP特异性CD8＋T淋巴细胞和CD4＋T淋巴细胞肝癌疫苗能有效阻止裸鼠皮下肿瘤的生长,治疗组（Lenti-AFP、AFP1、AFP542组）肿瘤直径[分别为（7.03±2.78）、（11.00±2.57）、（8.87±3.49） cm]低于对照组（F肿瘤直径=6.13,P＜0.01）,肿瘤重量[分别为（0.478±0.225）、（0.398±0.125）、（0.298±0.099）、（0.228±0.132）g],也低于对照组（F肿瘤重量=5.38,P＜0.01）.各治疗组不同程度上调裸鼠血清中IL-2、干扰素-γ、肿瘤坏死因子-α、穿孔素、颗粒酶B的水平,而对于T淋巴细胞活化的负调控因子IL-10,具有显著的抑制作用（P＜0.05）.结论 AFP特异性CD8＋ T/CD4＋T淋巴细胞疫苗能有效抑制荷人肝癌裸鼠体内肿瘤的生长.

Objective To study the posibility of hepatocellular carcinoma HCC） vaccines from dendritic cells （DCs） stimulated with alpha fetal protein （AFP） peptides or Lenti-AFP for hepatoceHular carcinoma （HCC） immunotherapy.Methods We created a lentivirus expressing AFP （Lenti-AFP） and AFP peptides liver tumor vaccines,and antitumor activity of AFP-specific HCC vaccines for tumor growth and related cytokines [interleukin （IL）-2,interferon （IFN）-γ,IL-10,tumor necrosis factor （TNF）-αt,perforin and granzyme B,FasL） were observed in 4 groups （Lenti-AFP,AFP1,AFP542 and control） in vivo.Results The AFP-specific tumor vaccines could efficiently kill HCC cells in vivo.The tumor diameter in control group was （12.28 ±3.49） cm,and that in treatment groups was （7.03 ±2.78）,（11.00 ±2.57）,（8.87 ±3.49） cm,respectively （FD =6.13,P〈0.01）.The tumor weight in control group was （0.478 ± 0.225） g,and that in treatment groups was （0.398 ± 0.125）,（0.298 ± 0.099）,（0.228 ±0.132） g respectively （Fw =5.38,P 〈 0.01）.The levels of IL-2,IFN-γ,TNF-α,perforin and granzyme B were increased to varying degrees,and those of IL-10 were significantly reduced in the treatment groups （P 〈0.05）.Conclusion AFP-specific CD8 ＋/CD4 ＋ T cells tumor vaccines which were activated by either Lenti-AFP-engineered or AFP peptide-pulsed DCs have obviously antitumor activity in vivo.This study provides new insight into the design of HCC immunotherapy.