Development and Validation of a TNF Family-Based Signature for Predicting Prognosis, Tumor Immune Characteristics, and Immunotherapy Response in Colorectal Cancer Patients.

Zheng Xiao,Tong Han,Dazun Shi,Weijun Peng,Kechao Nie,Zheyu Zhang,Lin Cheng,Jixin Zhong

doi:10.1155/2021/6439975

Abstract

In this study, a comprehensive analysis of TNF family members in colorectal cancer (CRC) was conducted and a TNF family-based signature (TFS) was generated to predict prognosis and immunotherapy response. Using the expression data of 516 CRC patients from The Cancer Genome Atlas (TCGA) database, TNF family members were screened to construct a TFS by using the univariate Cox proportional hazards regression and the least absolute shrinkage and selection operator- (LASSO-) Cox proportional hazards regression method. The TFS was then validated in a meta-Gene Expression Omnibus (GEO) cohort (n = 1162) from the GEO database. Additionally, the tumor immune characteristics and predicted responses to immune checkpoint blockade in TFS-based risk subgroups were analyzed. Eight genes (TNFRSF11A, TNFRSF10C, TNFRSF10B, TNFSF11, TNFRSF25, TNFRSF19, LTBR, and NGFR) were used to construct the TFS. Compared to the high-risk patients, the low-risk patients had better overall survival, which was verified by the GEO data. In addition, a high TFS risk score was associated with high infiltration of regulatory T cells (Tregs), nonactivated macrophages (M0), natural killer cells, immune escape phenotypes, poor immunotherapy response, and tumorigenic and metastasis-related pathways. Conversely, a low TFS risk score was related to high infiltration of resting CD4 memory T cells and resting dendritic cells, few immune escape phenotypes, and high sensitivity to immunotherapy. Thus, the eight gene-based TFS is a promising index to predict the prognosis, immune characteristics, and immunotherapy response in CRC, and our results also provide new understanding of the role of the TNF family members in the prognosis and treatment of CRC.

Highlights

Colorectal cancer (CRC) is the fourth leading cause of cancer-related mortality worldwide, with a high incidence rate [1]
A univariate Cox proportional hazards regression analysis was performed on the tumor necrosis factor (TNF) family gene expression data in the 516 CRC cases in the The Cancer Genome Atlas (TCGA) cohort
We investigated the immune profile in high- and low-risk patients and found that the TNF family-based signature (TFS) was closely associated with various tumor-infiltrating immune cells

Summary

Introduction

Colorectal cancer (CRC) is the fourth leading cause of cancer-related mortality worldwide, with a high incidence rate [1]. Radical resection is the gold standard treatment for CRC patients. Recent studies have demonstrated that pembrolizumab (an anti-PD-1 monoclonal antibody) had Journal of Immunology Research improved efficacy and long-term clinical benefit for the subgroup of patients with microsatellite instability-high (MSIH)/DNA mismatch repair-deficient (dMMR) CRC [7, 8]. As these immune checkpoint inhibitors have only exhibited clinical success in a small proportion of CRC patients [9], finding other immune checkpoint targets has important clinical implications

Methods

Results

Conclusion