Targeting TNFR2: A Novel Breakthrough in the Treatment of Cancer

Abstract

Tumor necrosis factor (TNF) receptor type II (TNFR2) is expressed in various tumor cells and some immune cells, such as regulatory T cells and myeloid-derived suppressing cells. TNFR2 contributes a lot to the tumor microenvironment. For example, it directly promotes the occurrence and growth of some tumor cells, activates immunosuppressive cells, and supports immune escape. Existing studies have proved the importance of TNFR2 in cancer treatment. Here, we reviewed the activation mechanism of TNFR2 and its role in signal transduction in the tumor microenvironment. We summarized the expression and function of TNFR2 within different immune cells and the potential opportunities and challenges of targeting TNFR2 in immunotherapy. Finally, the advantages and limitations of TNFR2 to treat tumor-related diseases are discussed, and the problems that may be encountered in the clinical development and application of targeted anti-TNFR2 agonists and inhibitors are analyzed.

Keywords: TNFR2; cancer treatment; immune checkpoint; immune response; signaling pathway; tumor immune microenvironment.

Figure 1

TNF/TNFR2 participates in various processes of tumor development by regulating different signaling pathways in the tumor and tumor microenvironment. TRAF2 and TRAF2-related proteins, such as TRAF1 and cIAP1/2, are recruited to activate TNFR2. Then, TNFR2 activates NF-κ B, STAT5, YAP, and other transcription factors through different pathways to induce the transcription of its target genes, thereby inhibiting tumor cell apoptosis and promoting the development of tumor cells. TNFR2 also participates in various changes in the tumor microenvironment through signal transduction such as JUNK, MLCK, and EGFR2. P, Phosphorylation.

Figure 2

Predictions of TNFR2 function in various cancers. (A) The TNFR2 expression profile across all tumor samples and paired normal tissues from the TCGA database through GEPIA. Each dot represents expression in samples. The red font represents the significantly high expression of TNFR2 in the tumor, and the green font represents the significantly low expression (P < 0.05). (B) Analysis of the relationship between the expression of TNFR2 and the overall survival (OS) of various cancer patients from the TCGA database through TISIDB. The red bar (longer) indicates a correlation between higher TNFR2 expression and better overall survival rates for cancer patients; the green bar (shorter) indicates a correlation between higher TNFR2 expression and decreased cancer patient overall survival rates; the blue bar (NS) indicates that the TNFR2 expression level is not correlated with the overall survival rate of cancer patients. (C) TNFR2 expression is related to patient disease-free survival (DFS) in various cancers. Data were obtained from the TCGA database through GEPIA (P < 0.05). The red represents a positive correlation between TNFR2 expression and disease-free survival in cancer patients, and the blue represents a negative correlation. (D, E) Using large-scale RNA-Seq data sets of multiple cancer types from the TCGA database, we analyzed the relationship between TNFR2 expression and tumor stage and grade through TIBIS prediction. The red bar (lower) indicates a correlation between higher TNFR2 expression and a lower stage or grade of cancer; the green bar (higher) indicates a correlation between higher TNFR2 expression and an increased cancer stage or grade; the blue bar (NS) indicates that the TNFR2 expression level is not correlated with the stage or grade of cancer.

Figure 3

Kaplan–Meier curves to demonstrate the clinic pathological significance of TNFR2. (A) Analysis of the relationship between the expression of TNFR2 and the overall survival (OS) of various cancer patients from TCGA database through TISIDB (P < 0.05). (B, C) Analysis of the relationship between TNFR2 expression and tumor stage and grade through TIBIS prediction (P < 0.05).

Figure 4

The relationship between different immune cells and immunomodulators and the expression of TNFR2 in various cancers. (A) Bioinformatics analysis of the correlation of TNFR2 expression and immune cell numbers. (B) The relationship between TNFR2 expression and immune inhibitors. (C, D) The correlation between TNFR2 and the expression of chemokines and their receptors. All data were obtained from the TCGA database through TISIDB.