{"title":"肿瘤衍生的 DEFB1 通过抑制树突状细胞成熟和损害 CD8+ T 细胞功能诱导食管鳞状细胞癌的免疫耐受。","authors":"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","doi":"10.21147/j.issn.1000-9604.2024.04.01","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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 <i>in vitro</i> experiments were then performed.</p><p><strong>Results: </strong>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 <i>in vitro</i>.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":9882,"journal":{"name":"Chinese Journal of Cancer Research","volume":"36 4","pages":"351-367"},"PeriodicalIF":7.0000,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11377887/pdf/","citationCount":"0","resultStr":"{\"title\":\"Tumor-derived DEFB1 induces immune tolerance by inhibiting maturation of dendritic cell and impairing CD8+ T cell function in esophageal squamous cell carcinoma.\",\"authors\":\"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\",\"doi\":\"10.21147/j.issn.1000-9604.2024.04.01\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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 <i>in vitro</i> experiments were then performed.</p><p><strong>Results: </strong>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 <i>in vitro</i>.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":9882,\"journal\":{\"name\":\"Chinese Journal of Cancer Research\",\"volume\":\"36 4\",\"pages\":\"351-367\"},\"PeriodicalIF\":7.0000,\"publicationDate\":\"2024-08-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11377887/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Chinese Journal of Cancer Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.21147/j.issn.1000-9604.2024.04.01\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chinese Journal of Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.21147/j.issn.1000-9604.2024.04.01","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
目的:CD8+ T 细胞是抗肿瘤免疫反应的关键效应细胞:CD8+ T细胞是抗肿瘤免疫反应中的关键效应细胞。食管鳞状细胞癌(ESCC)中 CD8+ T 细胞浸润的机制尚未明确阐明:方法:收集新鲜的 ESCC 组织,并根据 CD8+ T 细胞的浸润密度进行分组。在对这些样本进行转录组测序并与癌症基因组图谱(The Cancer Genome Atlas,TCGA)ESCC数据进行综合分析后,筛选出一种分泌蛋白DEFB1,以探讨其在CD8+ T细胞浸润中的潜在作用。然后进行了生物信息学分析、组织学验证和体外实验:结果:DEFB1在ESCC中高表达,且DEFB1的高表达是总生存率的独立危险因素。由于 DEFB1 的上调或下调并不影响 ESCC 细胞的增殖、迁移和凋亡,我们推测 DEFB1 的致癌作用是通过调节微环境特征实现的。生物信息学分析表明,DEFB1可能在炎症反应和抗肿瘤免疫反应中扮演重要角色,并与ESCC中未成熟树突状细胞(imDC)的浸润相关。组织学分析进一步证实,在DEFB1高表达的ESCC样本中,CD8+ T细胞浸润较少,CD83+成熟树突状细胞(mDC)浸润较少,而CD1a+ imDC浸润较多。用重组DEFB1蛋白处理后,DC的成熟明显受阻,随后T细胞在体外二维和三维培养中的杀伤作用也受到影响:结论:肿瘤来源的DEFB1能抑制DC的成熟并削弱CD8+ T细胞的功能,是ESCC免疫耐受的原因。DEFB1在ESCC中的作用值得进一步探讨。
Tumor-derived DEFB1 induces immune tolerance by inhibiting maturation of dendritic cell and impairing CD8+ T cell function in esophageal squamous cell carcinoma.
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.
期刊介绍:
Chinese Journal of Cancer Research (CJCR; Print ISSN: 1000-9604; Online ISSN:1993-0631) is published by AME Publishing Company in association with Chinese Anti-Cancer Association.It was launched in March 1995 as a quarterly publication and is now published bi-monthly since February 2013.
CJCR is published bi-monthly in English, and is an international journal devoted to the life sciences and medical sciences. It publishes peer-reviewed original articles of basic investigations and clinical observations, reviews and brief communications providing a forum for the recent experimental and clinical advances in cancer research. This journal is indexed in Science Citation Index Expanded (SCIE), PubMed/PubMed Central (PMC), Scopus, SciSearch, Chemistry Abstracts (CA), the Excerpta Medica/EMBASE, Chinainfo, CNKI, CSCI, etc.