西地那非对胃癌移植瘤小鼠髓源抑制细胞免疫活性的调节作用

Regulatory effects of sildenafil on myeloid derived suppressor cells in mice with gastric transplanted tumor

目的:探讨西地那非对胃癌移植瘤小鼠外周血髓源抑制细胞(myeloid derived suppressor cells,MDSCs)的比例以及免疫功能的调节机制。方法:建立胃癌MFC荷瘤小鼠模型,6周龄雌性615小鼠18只随机分为正常对照组、荷瘤PBS组和荷瘤西地那非组。接种移植瘤24 h后荷瘤西地那非组每天给予西地那非灌胃,荷瘤PBS组每天给予等体积的PBS灌胃。通过计算抑瘤率观察西地那非的体内抗肿瘤活性,应用流式细胞术检测外周血MDSC、T细胞亚群比例。结果与正常对照组比较,胃癌移植瘤小鼠外周血MDSC的比例升高(P<0.05),外周血CD4+/CD8+的比值降低(P<0.05)。外周血MDSC比例与CD4+/CD8+比值呈显著负相关(r=-0.858,P<0.01)。与荷瘤PBS组相比,西地那非可抑制胃癌移植瘤小鼠肿瘤生长,28 d后抑瘤率为41.2%,且可以降低荷瘤小鼠外周血MDSC的比例(P<0.05),提高外周血CD4+/CD8+的比值(P<0.05)。结论:胃癌移植瘤小鼠外周血MDSC比例升高,导致免疫功能紊乱。西地那非可能通过抑制MDSC数量,调节T细胞亚群的比例,增强抗肿瘤免疫,抑制肿瘤生长。

Objective： To study the regulatory mechanism of sildenafil on myeloid derived suppressor cells（MDSC） proportion in the peripheral blood and the changes of immune function in mice with gastric transplanted tumor.Methods： Mice were subcutaneously implanted with MFC tumor cells in the right back region.Eighteen female 615 mice aged six weeks were randomly divided into 3 groups： normal control group,tumor-bearing mice plus PBS group and tumor-bearing mice plus sildenafil group.The mice were transplanted with gastric tumor,after 24 hours,they were daily administered with sildenafil.Tumor-bearing mice plus PBS group were daily administered with the same volume of PBS.The antitumor activity of sildenafil was determined by calculating the tumor inhibitory rate.The proportion of MDSC and T lymphocyte subsets in peripheral blood were detected by flow cytometry.Results： Compared with normal control group,the proportion of MDSC in the peripheral blood was significantly increased（P＆lt;0.05）,and the ratio of CD4＋/CD8＋in the peripheral blood was decreased（P＆lt;0.05） in mice with gastric transplanted tumor.The proportion of MDSC was negatively correlated to CD4＋/CD8＋ratio（r=-0.858,P＆lt;0.01）.Compared with tumor-bearing mice plus PBS group,treatment with sildenafil could remarkably inhibit the tumor growth in mice with gastric transplanted tumor.After 28 days,the tumor inhibition rate was 41.2%.Moreover,the proportion of MDSC was decreased（P＆lt;0.05）,and the ratio of peripheral blood CD4＋/CD8＋ was increased（P＆lt;0.05）.Conclusion： An increase of the proportion of MDSC in the peripheral blood may lead to abnormality of immune function in mice with gastric transplanted tumor.Sildenafil might enhance antitumor immunity response and inhibit tumor growth by restraining the proportion of Gr1＋CD11b＋ myeloid derived suppressor cells and regulating the proportion of T cell subsets.