顺铂以T细胞依赖性方式增强CIK细胞的抗肿瘤作用  

Cisplatin pretreatment enhances the antitumor activity of cytokine-induced killer cells in a T cell-dependent manner

作　　者：黄香[1] 黄桂春[1] 宋海珠[1] 陈一天[1] 陈龙邦[1] 

机构地区：[1]南京大学医学院临床学院南京军区南京总医院肿瘤内科,南京210002

出　　处：《癌症进展》2011年第6期639-645,共7页Oncology Progress

基　　金：国家自然科学基金面上项目(No30872979);南京军区医学科研课题(09MA080)

摘　　要：目的观察顺铂预处理化疗联合细胞因子诱导的杀伤细胞(cytokine-induced killer cells,CIK cells)对小鼠CT-26结肠癌的抑制作用,并探讨介导顺铂免疫调节效作用的机制。方法分别建立BALB/c野生鼠或BALB/c nu/nu裸鼠CT-26结肠癌模型,以顺铂(Cisplatin,DDP)作为预处理方案。荷瘤小鼠随机分为四组:对照组(给予生理盐水,normal saline,NS)、CIK组(给予CIK细胞)、DDP组(给予DDP方案)、DDP-CIK组(DDP方案预处理后联合CIK细胞),隔日测量肿瘤长短径监测肿瘤体积。分离小鼠肿瘤组织,分别行CD3、FoxP3(Forkhead box P3)、CD31分子免疫组化染色以评估肿瘤组织局灶T淋巴细胞、Treg细胞的浸润情况以及肿瘤微血管密度的变化。流式细胞术观察DDP预处理化疗后荷瘤鼠脾脏组织中调节性T细胞(regulatory T cells,Treg cells)的动态变化。结果在BALB/c野生鼠CT-26结肠癌模型中,单独CIK免疫治疗或DDP化疗均可明显抑制CT-26结肠癌的生长(P<0.05),而DDP预处理化疗联合CIK细胞免疫治疗与单独化疗组相比,可显著的抑制CT-26结肠癌的生长(P<0.05)。在BALB/c裸鼠CT-26结肠癌模型中,DDP预处理化疗联合CIK细胞免疫治疗、单独CIK治疗及单独DDP化疗均不能抑制CT-26结肠癌的生长(P>0.05)。DDP预处理化疗均可促进CD3+T淋巴细胞至肿瘤局灶的浸润,下调肿瘤局灶及脾脏组织中Treg细胞的比例,而对肿瘤组织的微血管密度无明显作用。结论 DDP预处理化疗以T细胞依赖性方式增强CIK细胞对CT-26结肠癌的抑制作用。Objective To investigate the antitumor activity of cytokine-induced killer（CIK） cells following cisplatin（DDP） pretreatment in a murine CT-26 colon adenocarcinoma model and to elucidate the underlying mechanisms mediating the immunomodulating effect of DDP precondition.Methods BALB/c wild type and BALB/c nu/nu mice were challenged with CT-26 cells to establish colon adenocarcinoma modesl and then randomly divided into 4 groups.Control group： treated with normal saline（NS）;CIK group： administered with CIK cells;DDP group： administered with DDP;DDP-CIK group： administered with DDP followed by CIK cells.Tumor size and weight were used as indicators of therapeutic response.Immunohistochemistry was performed to observe the intratumoral infiltration of CD3＋ T lymphocytes and FoxP3＋ regulatory T（Treg） cells and tumor microvessel density.The dynamic changes of Treg cells in spleen tissues after DDP preconditioning chemotherapy were analyzed through flow cytometry.Results In CT-26 colon adenocarcinoma models,CIK cell therapy alone or DDP alone markedly inhibited the growth of CT-26 colon adenocarcinoma in BALB/c wild type mice（P 0.05）,and the combination of DDP preconditioning chemotherapy and CIK cells induced significant tumor growth retardation compared with single therapy（P0.05）.However,in BALB/c nu/nu mice,the combination therapy and both of the single therapies failed to induce significant tumor growth inhibition（P0.05）.DDP preconditioning chemotherapy in CT-26 colon adenocarcinoma model increased the level of T lymphocytes in local tumor tissues,decreased the percentages of Treg cells in tumor and spleen tissues,but exerted no influence on tumor microvessel density.Conclusion DDP preconditioning chemotherapy can enhance the antitumor activity of CIK cell therapy in CT-26 colon carcinoma mice.

关 键 词：预处理化疗 细胞因子诱导的杀伤细胞 免疫调节 调节性T细胞 

分 类 号：R735.35[医药卫生—肿瘤] R730.53[医药卫生—临床医学]