Abstract
BackgroundColorectal 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.MethodsUsing 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.ResultsA 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).ConclusionTNFRSF11B 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.
Highlights
In recent years, colorectal cancer has been the third leading cause of cancer-related death in the United States, with an incidence similar to that in China
Tumor necrosis factor receptor superfamily (TNFRSF) members consisting of TNFR2, glucocorticoid-induced tumor necrosis factor (GITR), TNFRSF4 (OX40), and TNFRSF9 (4-1BB) have been found to enhance T cell responses in the innate and adaptive immune systems as they act as costimulatory signals [5]
We demonstrated that the high-risk group had worse overall survival outcomes (p = 5.123∗e−7, Figure 2A) than the low-risk group, and the area under the curve (AUC) of the receiver operating characteristic (ROC) curve was 0.619 (Figure 2B), which supported the potential utility of the risk scoring system
Summary
Colorectal cancer has been the third leading cause of cancer-related death in the United States, with an incidence similar to that in China. Only approximately 15% of colorectal cancers, namely, those with microsatellite instability-high (MSI-H) status and mismatch repair deficiency (dMMR), referred to as ‘dMMR-MSI-H’, benefit from treatment with nivolumab due to the high proportion of tumor-infiltrating lymphocytes in these tumors [3]. The remaining 85% of colorectal cancers have microsatellite instability-low (MSI-L) status, microsatellite stable (MSS) status, and proficient mismatch repair (pMMR), referred to as ‘pMMRMSI-L’, and efficient immunotherapeutic strategies for these tumors are still lacking. Due to the low tumor mutation burden and low proportion of tumor-infiltrating lymphocytes in the microenvironment of pMMR-MSI-L tumors, researchers have recently proposed innovative therapeutic approaches, such as bispecific antibodies, T cell checkpoint inhibitors and T cell differentiation molecules [4]. 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
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