Fms样酪氨酸激酶3配体联合CpG和肿瘤抗原治疗肿瘤的研究

背景与目的:Fms样酪氨酸激酶3配体(fms-like tyrosine kinase 3 ligand,FLT3-L)、CpG虽可作为免疫调节剂发挥抗肿瘤作用,但单独用于治疗肿瘤效果不佳.本研究旨在探讨FLT3-L+肿瘤抗原+CpG联合应用对肝癌小鼠的治疗效果及机制,并探讨FLT3-L与GM-CSF在肿瘤治疗效果方面的差异.方法:选择小鼠H22肝癌模型为研究对象,分为FLT3-L+CpG组、GM-CSF+CpG组和PBS组.皮下注射给药后,用流式细胞术检测各组小鼠体内免疫细胞激活情况,免疫组化法检测肿瘤组织及局部细胞浸润情况,ELISA法检测小鼠体液免疫激活情况,同时观察各组小鼠生存期的差异,评价各组药物的抗肿瘤效果及可能的作用机制.结果:(1)FLT3-L+CpG组小鼠肿瘤生长明显被抑制,小鼠生存期显著延长,同GM-CSF+CpG组和PBS组相比差异具有统计学意义(P＜0.05).(2)脾脏淋巴细胞亚群分析显示,FLT3-L+CpG组CD3+T细胞比例显著上升,CD4+、CD8+亚群比例较PBS组与GM-CSF+CpG组均明显上升,CD4+CD25+Treg细胞比例明显下降,差异有统计学意义(P＜0.05).(3)肿瘤组织形态学分析显示,FLT3-L+CpG组可见大片的组织坏死和显著的淋巴细胞浸润.(4)肿瘤局部浸润淋巴细胞表型分析显示,FLT3-L+CpG组肿瘤局部NK细胞、DC细胞、CD8+T细胞明显增加,较各治疗组均有明显变化,与PBS相比差异有统计学意义(P＜0.05).(5)FLT3-L+CpG组与GM-CSF+CpG组小鼠体内细胞因子IFN-y、TNF-α、IL-2、IL-12均明显升高(P＜0.05).结论:FLT3-L+肿瘤抗原+CpG联合应用可发挥明显的抗肿瘤作用.此方案可能通过打破肿瘤免疫耐受,激活和增加循环中T细胞,并趋化NK细胞、DC细胞、CD8+T细胞到肿瘤局部,发挥杀伤肿瘤细胞的作用；同时可活化免疫因子网络,通过细胞免疫和体液免疫共同发挥抗肿瘤作用.

A novel investigation for cancer therapy based on the fms-like tyrosine kinase 3 ligand coimmunization with CpG and tumor antigen

Background and purpose:Fms-like tyrosine kinase 3 ligand(FLT3-L)and CpG can be used alone as a immunomodulators to play an antitumor effect,however their effect is not excellent.In this study,we explored the antitumor effect of FLT3-L,in combination with CpG and tumor antigen,and its mechanisms.Methods: The antitumor efficacy of FLT3-L was evaluated in BALB/c mice with established hepatoma.Mice were subcutaneous administrated of FLT3-L+CpG while the control groups were injected with PBS+CpG solution or GM-C...