替吉奥及MDSCs靶向干预剂对胆囊癌肿瘤微环境的影响

Influence of S-1 and MDSCs targeted intervention agent on gallbladder tumor microenvironment

目的 探讨化疗药物替吉奥和维生素D3等髓源性抑制细胞（MDSCs）靶向干预药物对胆囊癌肿瘤微环境的影响,为替吉奥及MDSCs靶向干预剂用于胆囊癌的临床治疗提供理论依据.方法 体外培养人胆囊癌细胞系NOZ,建立人源性胆囊癌裸鼠荷瘤动物模型,应用靶向干预MDSCs药物,运用流式细胞术筛选、鉴定、定量分析肿瘤组织微环境中MDSCs.结果 药物干预实验显示,对照组肿瘤组织平均体积大小2 246.4 mm3,而替吉奥组则为62.4 mm3,差异具有统计学意义（P＜0.05）,说明替吉奥能够明显抑制肿瘤细胞组织的生长,但对胆囊癌微环境中的MDSCs的影响微小.维生素D3组MDSCs表达比例为1.6％、COX-2抑制剂为1.6％,较对照组4.7％明显减少且差异具有统计学意义（P＜0.05）,说明维生素D3、COX-2抑制剂均能够明显降低胆囊癌微环境中MDSCs细胞的表达.在脾脏组织中,MDSCs亦呈相同变化趋势,其中维生素D3靶向干预效果更为明显.结论 靶向干预胆囊癌微环境中MDSCs表达能够改善肿瘤免疫逃逸状态,提示替吉奥化疗方案联合应用MDSCs靶向干预药物治疗胆囊癌具有可行性.

Objective To explore the effect on the gallbladder tumor microenvironment of chemotherapy drugs （gimeracil and oteracil porassium） S-1 and MDSCs targeted intervention drug such as vitamin D3 etc.To provide theoretical basis for clinical treatment of gallbladder cancer with S-1 in conjunction with MDSCs targeted intervention drugs.Methods Using the in vitro cultured human gallbladder cancer cells NOZ to establish anthropogenic tumor-burdened gallbladder cancer nude mice animal model,application of MDSCs drugs targeted intervention,using flow cytometry screening,identification and quantitative analysis of MDSCs in tumor microenvironment.Results Drug intervention trials showed that the mean tumor size of the control group was 2 246.44 mm3,while Gimeracil and Oteracil Porassium Capsules group was 62.40 mm3,and the difference was statistically significant （P 〈 0.05）,which showed that Gimeracil and Oteracil Porassium Capsules could significantly inhibit the growth of tumor cells and tissues,but its effect on MDSCs in the gallbladder microenvironment was slight; MDSCs expression ratio in vitamin D3 group was 1.6%,and COX-2 inhibitor group was 1.6%,compared with control group （4.7%）,the ratio decreased significantly,and the difference was statistically significant （P 〈 0.05）,which indicated that vitamin D3 and COX-2 inhibitors were able to reduce the expression of MDSCs cells in gallbladder cancer microenvironment significantly （P 〈 0.05）.In the spleen tissues,similar trend of MDSCs were also presented,while the the effect was more apparent in vitamin D3 targeted intervention group.Conclusions Targeted intervention the expression of MDSCs in gallbladder cancer microenvironment can improve state of tumor immune escape.S-1 in conjunction with MDSCs targeted intervention chemotherapy drugs in the treatment of the tumor of gallbladder is feasible.