Tumor-derived DEFB1 induces immune tolerance by inhibiting maturation of dendritic cell and impairing CD8+T cell function in esophageal squamous cell carcinoma  

作　　者：Jingjing Duan Haotian Wang Minglu Liu Yin Chen Ning Li Jieqiong Liu Lingxiong Wang Lin Li Yaru Liu Pengfei Dong Xiuxuan Wang Zhongyi Fan Shunchang Jiao 

机构地区：[1]Tianjin Medical University Cancer Institute and Hospital,National Clinical Research Center for Cancer,Tianjin’s Clinical Research Center for Cancer,Tianjin Key Laboratory of Digestive Cancer,Key Laboratory of Cancer Prevention and Therapy,Tianjin 300060,China [2]Department of Oncology,the Fifth Medical Center of Chinese PLA General Hospital,Beijing 100039,China [3]Beijing DCTY Biotech CO.,LTD.,Beijing 102200,China [4]Department of Biotherapy Center,Shenzhen Third People’s Hospital,Second Hospital Affiliated to Southern University of Science and Technology,Shenzhen 518112,China

出　　处：《Chinese Journal of Cancer Research》2024年第4期351-367,共17页中国癌症研究（英文版）

基　　金：supported by the National Natural Science Foundation of China(No.81972681,82103677);Tianjin Education Commission Research Plan Project(No.2021KJ201);Shenzhen High-level Hospital Construction Fund(No.G2022139);Tianjin Key Medical Discipline(Specialty)Construction Project(No.TJYXZDXK-009A).

摘　　要：Objective:CD8+T cells are the key effector cells in the anti-tumor immune response.The mechanism underlying the infiltration of CD8+T cells in esophageal squamous cell carcinoma(ESCC)has not been clearly elucidated.Methods:Fresh ESCC tissues were collected and grouped according to the infiltration density of CD8+T cells.After the transcriptome sequencing on these samples and the combined analyses with The Cancer Genome Atlas(TCGA)ESCC data,a secreted protein DEFB1 was selected to explore its potential role in the infiltration of CD8+T cells.Bioinformatics analyses,histological verification and in vitro experiments were then performed.Results:DEFB1 was highly expressed in ESCC,and the high expression of DEFB1 was an independent risk factor for overall survival.Since the up-regulation or down-regulation of DEFB1 did not affect the proliferation,migration and apoptosis of ESCC cells,we speculated that the oncogenic effect of DEFB1 was achieved by regulating microenvironmental characteristics.Bioinformatics analyses suggested that DEFB1 might play a major role in the inflammatory response and anti-tumor immune response,and correlate to the infiltration of immature dendritic cell(imDC)in ESCC.Histological analyses further confirmed that there were less CD8+T cells infiltrated,less CD83+mature DC(mDC)infiltrated and more CD1a+imDC infiltrated in those ESCC samples with high expression of DEFB1.After the treatment with recombinant DEFB1 protein,the maturation of DC was hindered significantly,followed by the impairment of the killing effects of T cells in both 2D and 3D culture in vitro.Conclusions:Tumor-derived DEFB1 can inhibit the maturation of DC and weaken the function of CD8+T cells,accounting for the immune tolerance in ESCC.The role of DEFB1 in ESCC deserves further exploration.

关 键 词：CD8+T cells DEFB1 dendritic cells esophageal squamous cell carcinoma tumor immune microenvironment 

分 类 号：R735.1[医药卫生—肿瘤]