Multi-omics Analysis of Tumor Necrosis Factor Superfamily 4 Reveals Its Prognostic Value and T Cell Exhaustion Feature in Cancer

Abstract

Abstract Background As a member of the Tumor Necrosis Factor (TNF) family, Tumor Necrosis Factor Superfamily 4 (TNFSF4) participated in various immune-related processes. Nevertheless, much is yet to be elucidated regarding the biological function of TNFSF4 in pan-cancer. Methods RNA-seq and corresponding clinical variables were gained from the Cancer Genome Atlas (TCGA). Immunotherapy cohorts were retrieved and downloaded from Gene Expression Omnibus (GEO). Tumor Immune Estimation Resource (TIMER) was used to evaluate tumor-infiltrating immune cell level in tumors. The Tumor Immune Single-cell Hub 2 (TISCH2) database was utilized to examine the expression of TNFSF4 across various tumor cell subsets. Gene Set Enrichment Analysis (GSEA) was utilized to explore related signaling pathways of TNFSF4. Results We utilized bioinformatic methods to analyze the TNFSF4 across TCGA cancers and found that TNFSF4 expression was highly increased in cancers compared to normal tissues. Further immunohistochemistry staining of multiple tumors validated this finding. Univariate Cox regression and survival analyses revealed that TNFSF4 served as a risk factor for a majority of cancer. Furthermore, TNFSF4 expression increased with the progression of tumor stage in multiple cancers. In the two immunotherapy cohorts from the GEO database, the proportion of PR/CR patients was higher in the TNFSF4 low-expression group. Through integrating single-cell data from the TISCH database, we found that TNFSF4 expression was predominantly observed in proliferative T cells and exhausted T cells. Correlation analysis demonstrated that TNFSF4 was positively associated with a range of immunomodulatory genes. Ultimately, analysis of GSEA revealed that TNFSF4 was related to immune response and EMT pathways. Conclusions We identified the function of TNFSF4 as a valuable molecule for cancer, and its capacity to predict response of immunotherapy. Importantly, our work revealed a robust association between TNFSF4 and exhausted T cells within the tumor microenvironment, which indicated TNFSF4 may be a promising biomarker for cancer treatment.