Antitumor immunity of low-dose cyclophosphamide:changes in T cells and cytokines TGF-beta and IL-10 in mice with colon-cancer liver metastasis  

低剂量环磷酰胺的抗肿瘤免疫:结肠癌肝转移治疗后T细胞、转移生长因子β及白介素10的改变

作　　者：Xiao-Ming Huang Nan-Rong Zhang Xu-Tao Lin Cai-Yan Zhu Yi-Feng Zou Xiao-Jian Wu Xiao-Sheng He Xiao-Wen He Yun-Le Wan Ping Lan 

机构地区：[1]Department of Hepatobiliary Surgery,The Sixth Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong,P.R.China [2]Guangdong Institute of Gastroenterology,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases,The Sixth Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong,P.R.China [3]Department of Anesthesiology,The Sixth Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong,P.R.China [4]Department of Gastrointestinal Endoscopy,Department of Colorectal Surgery,The Sixth Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong,P.R.China [5]Department of Pharmacy,The Sixth Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong,P.R.China [6]Department of Colorectal Surgery,The Sixth Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong,P.R.China

出　　处：《Gastroenterology Report》2020年第1期56-65,I0002,共11页胃肠病学报道（英文）

基　　金：This work was supported by National Key Clinical Discipline,the Fundamental Research Funds for the young teacher training program of Sun Yat-sen University[grant number 18ykpy02];Medical Scientific Research Foundation of Guangdong Province of China[grant number A2016198];‘5010 Clinical Research Programme’of Sun Yat-sen University[grant number 2010012].

摘　　要：Background:The tumor immune microenvironment is one of the most important prognostic factors in liver metastasis from colorectal cancer.Low-dose cyclophosphamide(CTX)is widely believed to be involved in the modulation of the immune system.However,the underlying mechanism of low-dose CTX remains unknown.This study aimed to investigate the antitumor immunity of low-dose CTX in the treatment of colon-cancer liver metastasis.Methods:Thirty mice were randomly divided into five groups.After liver metastasis was established in colon-cancer models,mice in the treatment groups were injected with low-dose CTX(20 mg/kg)at different time points.Liver and spleen tissues were examined for T-cell markers via flow cytometry.Interleukin(IL)-10 and transforming growth factor(TGF)-b1 expression levels in liver tissues were analysed by immunohistochemistry.Serum interferon(IFN)-c and IL-10 levels were detected by enzyme-linked immunosorbent assay.An additional 20 mice were randomly allocated into two groups and the survival times were recorded.Results:The expression levels of CD4^(+)T cells,CD8^(+)T cells,and IFN-c were down-regulated,whereas those of IL-10 and TGF-b1 were up-regulated in liver metastasis from colon cancer in mice.Furthermore,the local and systemic microenvironments of the liver were altered,which led to reduced antitumor immune responses and subsequently liver metastasis.However,treatment with low-dose CTX reversed these effects.The survival times of mice treated with low-dose CTX were significantly longer than those of the other groups.Conclusions:Low-dose CTX exerts its antitumor activity by changing the systemic and local immune microenvironments and enhancing immune regulation inmice.CTX could be used as a drug to prevent and treat livermetastasis from colon cancer.背景:肿瘤免疫微环境是结直肠癌肝转移最重要的预后因素之一。低剂量环磷酰胺(CTX)被认为可以调节免疫系统,然而,其调节机制尚不明了。本研究旨在研究低剂量CTX治疗结直肠癌肝转移时的抗肿瘤免疫特性。方法:将30只小鼠随机分为5组。在结肠癌肝转移模型建立后,治疗组在不同时间点注射低剂量CTX(20 mg/kg)。取肝脏和脾脏组织,通过流式细胞方法检测T细胞标志物;通过免疫组化方法分析肝脏组织中白介素(IL)10和转化生长因子(TGF)β1表达水平。采用酶联免疫吸附实验检测血清干扰素(IFN)γ和IL-10水平。另取20只小鼠随机分为治疗组和对照组,记录其存活情况。结果:结直肠癌肝转移组小鼠CD4^(+)T细胞、CD8^(+)T细胞及IFN-γ表达水平均下调,但IL-10和TGF-β1表达上调。而且,肝转移小鼠肝脏的局部及系统免疫微环境均发生了变化,导致抗肿瘤免疫反应减弱,从而出现肝转移。然而,低剂量CTX治疗可以逆转上述情况。低剂量CTX组小鼠的生存时间显著延长。结论:低剂量CTX可以通过改变系统及局部的免疫微环境、增强免疫调控而发挥抗肿瘤作用。CTX或可用于结肠癌肝转移的预防和治疗。

关 键 词：colon cancer liver metastasis CYCLOPHOSPHAMIDE immune microenvironment 

分 类 号：R735.37[医药卫生—肿瘤]