Ad(E1-).sT治疗乳腺癌移植瘤的作用及体内免疫激活效应  

Therapeutic effects and immune activation of TGF-β targeted recombinant Ad(E1-).sT in breast cancer

作　　者：王浩 杨月峰 胡泽斌[2] 王华 肖凤君 王立生 WANG Hao;YANG Yue-feng;HU Ze-bin;WANG Hua;XIAO Feng-jun;WANG Li-sheng(Department of Experimental Hematology,Beijing Institute of Radiation Medicine,Beijing 100850,China)

机构地区：[1]军事科学院军事医学研究院辐射医学研究所实验血液学与生物化学研究室,北京100850 [2]中国食品药品检定研究院体外诊断试剂所,北京100050

出　　处：《中国医药生物技术》2018年第4期294-299,共6页Chinese Medicinal Biotechnology

基　　金：国家自然科学基金(81402558;81472396);北京市科技新星计划(Z171100001117118)

摘　　要：目的研究复制缺陷型腺病毒Ad(E1-).s T治疗小鼠乳腺癌移植瘤的作用,探讨Ad(E1-).sT的免疫激活效应。方法指数生长期的小鼠乳腺癌细胞4T1按2×10~6细胞/100μl PBS皮下荷瘤4～6周龄的BALB/c小鼠,建立具有完全免疫系统的乳腺癌移植瘤模型。荷瘤后第7天,将成瘤小鼠分为Buffer治疗组、Ad(E1-).Null治疗组和Ad(E1-).s T治疗组,分别瘤内给予PBS、Ad(E1-).Null和Ad(E1-).s T(2.5×10^(10) VPs/小鼠)进行治疗;第10天,重复治疗一次。于第7、12、15、19天,分别测定肿瘤体积,绘制肿瘤生长曲线,于第12、18天,内眦静脉取血,检测小鼠血象和外周血T淋巴细胞亚型;于第19天处死小鼠,剥离肿瘤,测定肿瘤重量,并分离脾脏细胞,测定树突状细胞(DCs)的比例和数量。结果 Ad(E1-).s T治疗能够有效抑制乳腺癌移植瘤的生长,抑制肿瘤重量的增加。在机制上,Ad(E1-).s T能够调节小鼠外周血的血象,抑制淋巴细胞、粒细胞和中间细胞的增长;同时,Ad(E1-).s T能够促进T淋巴细胞的成熟和分化,降低未成熟淋巴细胞的比例,促进CD4^+T淋巴细胞和CD8+T淋巴细胞的增殖。此外,Ad(E1-).s T还增强小鼠脾脏DCs的扩增与成熟。结论 Ad(E1-).s T可通过调节机体抗肿瘤免疫反应,抑制乳腺癌移植瘤的生长。Objective To evaluate the therapeutic effects of replication-deficiency adenovirus Ad(E1-).sT in mouse breast cancer xenograft,and to study immune responses induced by Ad(E1-).sT.Methods To establish breast cancer xenograft model with competent immune system,4T1(2×106/100μl PBS)at the state of exponential growth of mouse breast cancer cells were injected into the 4-6 weeks-old BALB/c mouse subcutaneously.Mice bearing tumor were divided into 3 groups:Buffer group,Ad(E1-).Null group and Ad(E1-).sT group.On day 7 and 10,PBS,Ad(E1-).Null and Ad(E1-).sT(2.5×1010 VPs per mouse)were administrated intratumorally twice,respectively.The tumor volume was monitored on day 7,12,15 and 19,and the tumor growth curve was drawn.On day 12 and 18,anticoagulant peripheral blood samples were collected via venae angularis.Then,the hemogram in peripheral blood and subtypes of T lymphocytes were analyzed.The mice were euthanized on day 19,and the tumors were removed and weighed.Moreover,the spleens were also removed and single cell suspensions were prepared.The percentage and numbers of dendritic cells(DCs)in spleens were analyzed.Results Ad(E1-).sT efficiently inhibited growth of breast cancer xenograft,and also reduced tumor weight at the terminal time point.Ad(E1-).sT could regulated the hemogram in peripheral blood,such as inhibiting the increase of lymphocytes,granulocytes and intermediate cells.Meanwhile,Ad(E1-).sT also promoted the maturation and differentiation of T lymphocytes,down-regulated percentage of immature T lymphocytes,and increased proliferation of CD4+T and CD8+T lymphocytes.In addition,Ad(E1-).sT also enhanced growth and maturation of DCs in mouse spleen.Conclusion Ad(E1-).sT inhibits the growth of breast cancer xenograft through regulating anti-tumor immune responses in mice.

关 键 词：乳腺癌 复制缺陷型腺病毒 转化生长因子β 免疫激活 

分 类 号：R737.9[医药卫生—肿瘤]