GRA15_(Ⅱ)在小鼠肿瘤微环境中促进巨噬细胞极化抗肝癌  

GRA15_(Ⅱ)Against Hepatic Carcinoma in Mice via Promotion of Macrophage Polarization in Tumor Microenvironment

作　　者：余焱霞 张远 王艳玲 蔡亦红[1,2,3] YU Yanxia;ZHANG Yuan;WANG Yaning;CAI Yihong(Department of Health Inspection and Quarantine,Anhui Medical University,Hefei 230032,China;Department of Pathogen Biology and Provincial Laboratories of Pathogen Biology and Zoonoses,Hefei 230032,China;Department of Laboratory Science,Hefei 230032,China)

机构地区：[1]安徽医科大学公共卫生学院卫生检验与检疫,合肥230032 [2]安徽医科大学病原生物学安徽省重点实验室,合肥230032 [3]安徽医科大学人畜共患病安徽高校省级重点实验室,合肥230032

出　　处：《中国动物传染病学报》2024年第1期36-47,共12页Chinese Journal of Animal Infectious Diseases

基　　金：国家自然科学基金(81572801)。

摘　　要：肿瘤相关巨噬细胞(TAM)与肿瘤的转归密切相关,探索刚地弓形虫致密颗粒蛋白分子(GRA15_(Ⅱ))在肿瘤微环境中通过诱导巨噬细胞(Mφ)极化抑制肿瘤生长的作用机制。通过构建肝细胞癌小鼠,注射LV-gra15_(Ⅱ)重组慢病毒后,采用实时荧光定量PCR、酶联免疫法、免疫组化、流式细胞术和共聚焦显微镜分析肿瘤微环境中的免疫应答情况。结果显示,GRA15_(Ⅱ)可在体外诱导M2样Mφ向M1表型偏移。而且,在荷瘤小鼠注射LV-gra15_(Ⅱ)后,肿瘤体积明显减小,进一步分析发现,在肿瘤微环境中GRA15_(Ⅱ)主要通过TRAF6途径激活NF-κB,诱导TAM从M2向M1偏移,且NO、IL-12、TNF-α的表达上调,发挥Th1免疫应答。GRA15_(Ⅱ)能够抑制肿瘤生长,此研究为肿瘤免疫治疗提供新的思路和策略,为开发新的药物提供实验室基础。Tumor-associated macrophages(TAMs)play an important role in the development of tumors.The aim of the present study was to investigate the role of the dense granule protein molecule of Toxoplasmagondii(GRA15_(Ⅱ))in inhibition of the tumor growth via macrophage polarization.Here,we constructed a recombinant LV-GRA15_(Ⅱ)and injected it into tumor bearing C57BL/6 mice for analyzing the immune responses in tumor microenvironment by RT-PCR,ELISA,IHC,FCM and LSCM.GRA15_(Ⅱ)induced the repolarization of M2-like macrophages without affecting the M1 phenotype invitro.Additionally,GRA15_(Ⅱ)inhibited the tumor growth and induced the TAM polarization from M2-like to M1-like by TRAF6-NF-κB pathway activation.Furthmore,expression of NO,IL-12 and TNF-αwas upregulated to enhance Th1 immune response in the tumor microenvironment.In conclusion,GRA15_(Ⅱ)inhibited the tumor growth,which might lead to new immunotherapy strategies and experimental research for the development of new drugs to tumor treatment.

关 键 词：弓形虫 致密颗粒蛋白 肝细胞癌 巨噬细胞 极化 

分 类 号：R730.51[医药卫生—肿瘤]