表达IL-15的溶瘤病毒在胃癌中的抗肿瘤活性研究

Antitumor Activity of Oncolytic Viruses Expressing IL-15 in Gastric Cancer

目的探索表达IL-15的VSVΔ51溶瘤病毒在胃癌中的抗肿瘤活性。方法获得鼠IL-15基因序列,并将其整合到VSVΔ51溶瘤病毒的骨架中,获得VSVΔ51/IL-15重组溶瘤病毒。通过体外感染肿瘤细胞,验证其溶瘤活性。同时在体内移植瘤模型中给予VSVΔ51/IL-15治疗,根据肿瘤抑制能力监测,免疫组化分析T细胞浸润及流式分析浸润T细胞的抗肿瘤免疫激活情况,来反应VSVΔ51/IL-15的抗肿瘤活性。结果构建并获得了VSVΔ51/IL-15溶瘤病毒,体外实验表明其可以有效感染肿瘤细胞并表达IL-15(P<0.01),而且存在剂量依赖性细胞毒性。体内移植瘤抗肿瘤实验表明,VSVΔ51/IL-15可以显著抑制肿瘤生长(P<0.01),减少肿瘤细胞有丝分裂能力。免疫组化结果表明,VSVΔ51/IL-15可以显著增强T细胞浸润(P=0.000),流式结果则反映出VSVΔ51/IL-15治疗后的肿瘤浸润T细胞具有更强的抗肿瘤活性(P=0.000)。结论VSVΔ51/IL-15可以显著抑制胃癌细胞生长,增强抗肿瘤免疫反应,有可能为胃癌的治疗提供新的策略。

Objective To explore the antitumor activity of VSVΔ51 oncolytic virus expressing IL-15 in gastric cancer.Methods The sequence of mouse IL-15 gene was obtained and integrated into the skeleton of VSVΔ51 oncolytic virus to obtain VSVΔ51/IL-15 oncolytic virus.The oncolytic activity of tumor cells was verified by infecting tumor cells in vitro.At the same time,VSVΔ51/IL-15 was given to the tumor xenograft model in vivo.The anti-tumor activity of VSVΔ51/IL-15 was reflected by the tumor inhibition ability test,immunohistochemical analysis of T cell infiltration and flow analysis of anti-tumor immune activation of infiltrating T cells.Results VSVΔ51/IL-15 oncolytic virus was constructed and obtained.In vitro experiments showed that it could effectively infect tumor cells and express IL-15(P<0.01),it could also lyse tumor cells in a dose-dependent manner.The anti-tumor experiment of the tumor xenograft model showed that VSVΔ51/IL-15 could significantly inhibit tumor growth(P<0.01)and reduce the mitotic ability of tumor cells.Immunohistochemical results showed that VSVΔ51/IL-15 could significantly enhance T cell infiltration(P=0.000),while flow cytometry showed that tumor infiltrating T cells treated with VSVΔ51/IL-15 had stronger anti-tumor activity(P=0.000).Conclusion VSVΔ51/IL-15 can significantly inhibit the growth of gastric cancer cells and enhance anti-tumor immune response,which may provide a new strategy for the treatment of gastric cancer.