结直肠癌是世界范围内的致命癌症。由于肿瘤突变负荷低,肿瘤浸润淋巴细胞在大多数患者微环境中的比例低,需要确定创新的免疫治疗方法。
使用TCGA-COAD数据集(n=514),我们确定TNFRSF11B是结肠癌的预后因素.免疫组织化学(IHC)数据集(n=86),290个单个结直肠癌细胞(GSE81861),并进一步应用31个配对的结肠癌转录数据集来验证TNFRSF11B的功能,通过荧光激活细胞分选(FACS)分析证实。
由八个免疫相关基因(IRGs)组成的风险评分系统(FGFR2,ZC3HAV1L,TNFRSF11B,CD79A,IGHV3-11,IGHV3-21,IGKV2D-30和IGKV6D-21)被构建用于预测结肠癌患者的预后。只有TNFRSF11B与晚期淋巴结转移和较差的生存预后密切相关(p=0.010,p=0.014和p=0.0061)。在我们的IHC数据集中,72.09%(62/86)的结肠癌患者有TNFRSF11B过表达,总生存时间显著缩短(p=0.072)。高TNFRSF11B表达通常具有较晚的TNM阶段(p=0.067),淋巴结(p=0.029)和淋巴管(p=0.007)侵袭的频率较高,肺炎的发病率较高(p=0.056)。六个基因(KRT18,ARPC5L,ACTG1,ARPC2,EZR,通过基因集富集分析(GSEA),与致病性大肠杆菌感染相关的YWHAZ)与TNFRSF11B过表达同时增加。这些基因参与肌动蛋白细胞骨架的调节,志贺氏菌病,细菌入侵上皮细胞,和沙门氏菌感染。最后,仅活化的记忆性CD4+T细胞(p=0.017)在TNFRSF11B高表达组中显著降低,TCGA-COAD数据集的TIMER2.0分析证实了这一点。我们还进行了FACS分析,以显示TNFRSF11B降低了结直肠癌微环境中中枢记忆CD4+T细胞和效应记忆CD4+T细胞的浸润(所有p<0.001)。
TNFRSF11B可作为结肠癌患者的预后因子,并可能影响结肠癌的免疫反应。TNFRSF11B与淋巴结侵袭和致病性大肠杆菌密切相关。感染,这可能会对结肠癌中记忆激活的CD4+T细胞浸润产生负面影响。
Colorectal cancer is a lethal cancer worldwide. Due to the low tumor mutation burden and low proportion of tumor-infiltrating lymphocytes in the microenvironment of most patients, innovative immunotherapeutic approaches need to be identified.
Using the TCGA-COAD dataset (n = 514), we identified
TNFRSF11B as a prognostic factor of colon cancer. An immunohistochemistry (IHC) dataset (n = 86), 290 single colorectal cancer cells (GSE81861), and 31 paired colon cancer transcriptional datasets were further applied to validate the function of TNFRSF11B, which was confirmed via fluorescence-activated cell sorting (FACS) analysis.
A risk score system consisting of eight immune-related genes (IRGs) (FGFR2, ZC3HAV1L,
TNFRSF11B, CD79A, IGHV3-11, IGHV3-21, IGKV2D-30, and IGKV6D-21) was constructed to predict the prognosis of colon cancer patients. Only
TNFRSF11B was closely correlated with late-stage lymph node metastasis and worse survival outcomes (p = 0.010, p = 0.014, and p = 0.0061). In our IHC dataset, 72.09% (62/86) of the colon cancer patients had TNFRSF11B overexpression with significantly shorter overall survival times (p = 0.072). High
TNFRSF11B expression typically had a later TNM stage (p = 0.067), a higher frequency of lymph node (p = 0.029) and lymphovascular (p = 0.007) invasion, and a higher incidence of pneumonia (p = 0.056) than their counterparts. The expression of six genes (KRT18, ARPC5L, ACTG1, ARPC2, EZR, and YWHAZ) related to pathogenic E. coli infection was simultaneously increased with TNFRSF11B overexpression via gene set enrichment analysis (GSEA). These genes are involved in the regulation of the actin cytoskeleton, shigellosis, bacterial invasion of epithelial cells, and Salmonella infection. Finally, only activated memory CD4+ T cells (p = 0.017) were significantly decreased in the high TNFRSF11B expression group via CIBERSORT comparison, which was confirmed by TIMER2.0 analysis of the TCGA-COAD dataset. We also performed FACS analysis to show that TNFRSF11B decreased the infiltration of central memory CD4+ T cells and effector memory CD4+ T cells in the colorectal cancer microenvironment (all p <0.001).
TNFRSF11B acts as a prognostic factor for colon cancer patients and could affect the colon cancer immune response. TNFRSF11B was closely related to lymph node invasion and pathogenic E. coli. infection, which may negatively affect memory-activated CD4+ T cell infiltration in colon cancer.