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Updated: Oct 9, 2025
Molecular Profiling of the Invasive Tumor Microenvironment in a 3-Dimensional Model of Colorectal Cancer Cells and Ex vivo Fibroblasts
Published on: April 29, 2014
TNFRSF11B Suppresses Memory CD4+ T Cell Infiltration in the Colon Cancer Microenvironment: A Multiomics Integrative
Jun-Rong Zhang1, Ping Hou2, Xiao-Jie Wang3
1Department of General Surgery (Emergency Surgery), Fujian Medical University Union Hospital, Fuzhou, China.
Background:
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.
Methods:
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.
Results:
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).
Conclusion:
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.
Insights
TNFRSF11B is a prognostic factor in colon cancer, linked to lymph node invasion and reduced T-cell infiltration. This finding offers new avenues for colon cancer immunotherapy development.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Colorectal cancer (CRC) poses a significant global health challenge.
- Most CRC cases exhibit low tumor mutation burden and limited tumor-infiltrating lymphocytes, necessitating novel immunotherapeutic strategies.
Purpose of the Study:
- To identify novel prognostic factors and therapeutic targets for colon cancer.
- To investigate the role of TNFRSF11B in colon cancer progression and immune microenvironment.
Main Methods:
- Utilized TCGA-COAD dataset (n=514) to identify TNFRSF11B as a prognostic factor.
- Validated TNFRSF11B function using immunohistochemistry (n=86), single-cell RNA sequencing (n=290), and paired transcriptional datasets (n=31).
- Employed fluorescence-activated cell sorting (FACS) for functional validation and CIBERSORT/TIMER2.0 for immune cell infiltration analysis.
Main Results:
- TNFRSF11B overexpression correlated with advanced TNM stage, lymph node metastasis, and poorer survival outcomes.
- High TNFRSF11B expression was associated with increased risk of pneumonia and pathogenic Escherichia coli infection.
- TNFRSF11B significantly reduced the infiltration of activated memory CD4+ T cells in the colorectal cancer microenvironment.
Conclusions:
- TNFRSF11B serves as a critical prognostic biomarker in colon cancer.
- TNFRSF11B influences the tumor immune microenvironment, potentially by impairing CD4+ T cell responses.
- Targeting TNFRSF11B may represent a promising strategy for enhancing colon cancer immunotherapy.
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