摘要
目的:探讨恶性肿瘤中Dickkopf-1(DKK1)表达对CD4^(+)T细胞极化的影响及其作为肿瘤免疫治疗靶点的潜在价值。方法:利用生物信息学方法分析DKK1在多种类型肿瘤组织和癌旁组织中的表达水平,分析DKK1表达与肿瘤患者预后及肿瘤微环境免疫浸润间的相关性。利用流式细胞术检测DKK1蛋白对CD4^(+)T细胞表型变化的影响。构建黑色素瘤B16F10细胞小鼠皮下移植瘤模型,观察阻断DKK1对小鼠移植瘤生长和移植瘤组织中免疫细胞浸润与表型的影响。结果:DKK1 mRNA表达水平在多种肿瘤组织中显著高于癌旁组织,DKK1高表达与多数肿瘤患者的不良预后相关且在多数肿瘤中DKK1对CD4^(+)T细胞抗肿瘤免疫应答功能有重要负性调节作用(P<0.05或P<0.01)。流式细胞术检测结果显示,DKK1蛋白刺激可显著降低CD4^(+)T细胞中T-bet、IFN-γ及CD107a表达水平(均P<0.01)。在小鼠皮下黑色素瘤模型中发现,阻断DKK1可以显著抑制小鼠移植瘤的生长(P<0.01),有效改善抗肿瘤免疫应答,表现为Th1细胞(T-bet+CD4^(+))占比显著升高(P<0.001),效应性CD8^(+)T细胞(CD44+CD62L-)占比显著升高(P<0.01),Th2细胞(GATA3^(+)CD4^(+))与Treg细胞占比显著下降(均P<0.01)。结论:阻断DKK1可有效促进CD4^(+)T细胞向Th1型极化,DKK1具有作为肿瘤免疫治疗靶点的潜在价值。
Objective:To explore the effect of Dickkopf-1(DKK1)expression on CD4^(+)T cell polarization in malignant tumors and its potential value as a target for cancer immunotherapy.Methods:Bioinformatics algorithm was used to analyze the expression of DKK1 in multiple types of tumor tissues and adjacent tissues,and the correlation between the expression of DKK1 and the prognosis of cancer patients and immune infiltration of tumor microenvironment.The effect of DKK1 protein on the phenotype of CD4^(+)T cells was analyzed by flow cytometry in vitro.A melanoma B16F10 cell mouse subcutaneous transplantation tumor model was established to observe the effects of blocking DKK1 on the growth of mouse transplantation tumor and immune cell infiltration and phenotype in transplantation tumor tissues.Results:The mRNA expression levels of DKK1 in many kinds of tumor tissues were significantly higher than those in adjacent tissues.High expression of DKK1 was related to the poor prognosis of most tumor patients.In most types of tumors DKK1 played important negative regulatory role in CD4^(+)T cell anti-tumor immune response(P<0.05 or P<0.01).The results of flow cytometry in vitro showed that DKK1 protein stimulation significantly decreased the expression levels of T-bet,IFN-γand CD107a in CD4^(+)T cells(all P<0.01).In the mouse subcutaneous melanoma model,it was found that blocking DKK1 could significantly inhibit the growth of transplanted tumors(P<0.01)and effectively improve the anti-tumor immune responses including the proportion of Th1 cells(T-bet+CD4^(+))increasing significantly(P<0.001),the proportion of effector CD8^(+)T cells(CD44+CD62L-)increasing significantly(P<0.01),and the proportion of Th2 cells(GATA3^(+)CD4^(+))and Treg cells decreasing significantly(both P<0.01).Conclusion:Blocking DKK1 can effectively promote the phenotypic polarization of CD4^(+)T cells to Th1.DKK1 has potential value as a target for tumor immunotherapy.
作者
周啸宇
施涛
张翼鹏
宋雪如
罗钰婷
魏嘉
ZHOU Xiaoyu;SHI Tao;ZHANG Yipeng;SONG Xueru;LUO Yuting;WEI Jia(Department of Oncology,Nanjing Drum TowerHospital,Drum Tower Clinical Medical College,Nanjing University of Chinese Medicine,Nanjing 210000,Jiangsu,China;Departmentof Oncology,Nanjing Drum Tower Hospital,Affiliated Hospital of Medical School,Nanjing University,Nanjing 210000,Jiangsu,China)
出处
《中国肿瘤生物治疗杂志》
CAS
CSCD
北大核心
2024年第7期662-668,共7页
Chinese Journal of Cancer Biotherapy
基金
国家自然科学基金面上项目(No.82373263)
江苏省科技计划专项资金(基础研究计划自然科学基金)青年基金项目(No.BK20230151)。
