AUTHOR=Zhang Jun-rong , Hou Ping , Wang Xiao-jie , Weng Zong-qi , Shang-guan Xin-chang , Wang Hui , You Fang , Lin Bing-qiang , Huang Zheng-yuan , Chen Xian-qiang 

TITLE=TNFRSF11B Suppresses Memory CD4+ T Cell Infiltration in the Colon Cancer Microenvironment: A Multiomics Integrative Analysis

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.742358

DOI=10.3389/fimmu.2021.742358

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>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.</p></sec><sec><title>Methods</title><p>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 <italic>via</italic> fluorescence-activated cell sorting (FACS) analysis.</p></sec><sec><title>Results</title><p>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 (<italic>p</italic> = 0.010, <italic>p</italic> = 0.014, and <italic>p</italic> = 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 (<italic>p</italic> = 0.067), a higher frequency of lymph node (<italic>p</italic> = 0.029) and lymphovascular (<italic>p</italic> = 0.007) invasion, and a higher incidence of pneumonia (<italic>p</italic> = 0.056) than their counterparts. The expression of six genes (KRT18, ARPC5L, ACTG1, ARPC2, EZR, and YWHAZ) related to pathogenic <italic>E. coli</italic> infection was simultaneously increased with TNFRSF11B overexpression <italic>via</italic> 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<sup>+</sup> T cells (<italic>p</italic> = 0.017) were significantly decreased in the high TNFRSF11B expression group <italic>via</italic> 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<sup>+</sup> T cells and effector memory CD4<sup>+</sup> T cells in the colorectal cancer microenvironment (all <italic>p &lt;</italic>0.001).</p></sec><sec><title>Conclusion</title><p>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 <italic>E. coli</italic>. infection, which may negatively affect memory-activated CD4+ T cell infiltration in colon cancer.</p></sec>