Tnfsf4

What is TNFSF4 protein?

TNFSF4 gene (TNF superfamily member 4) is a protein coding gene which situated on the long arm of chromosome 1 at locus 1q25. TNFSF4 is a protein that belongs to the tumor necrosis factor (TNF) ligand family. It plays a role in T cell-antigen-presenting cell (APC) interactions and is involved in mediating the adhesion of activated T cells to endothelial cells. This cytokine has the capability to bind to TNFRSF4 and co-stimulates T-cell proliferation and cytokine production. Furthermore, TNFSF4 has been identified as a potential target for immunotherapy, particularly in the context of breast carcinomas, due to its aberrant expression patterns and its association with shorter overall survival and disease-free survival. The TNFSF4 protein is consisted of 183 amino acids and TNFSF4 molecular weight is approximately 21.1 kDa.

What is the function of TNFSF4 protein?

TNFSF4, also known as OX40 Ligand, binds to its receptor TNFRSF4 (OX40), which is predominantly expressed on activated T cells. This interaction provides a co-stimulatory signal that enhances T cell proliferation, survival, and cytokine production. By engaging with its receptor, TNFSF4 helps regulate the immune response, promoting the differentiation of T cells into effector and memory cells, which is critical for long-term immunity. High expression of TNFSF4 is associated with shorter overall survival and disease-free survival, and it is considered a potential target for immunotherapy due to its ability to reactivate the immune response and potentially inhibit cancer stem cells. TNFSF4 has been found to correlate with ALDH1A1 expression, which is associated with cancer stem cells.

Fig1. Downstream effects of OX40-OX40L signaling. (Kaviyon Sadrolashrafi, 2024)

TNFSF4 Related Signaling Pathway

TNFSF4 binds to its receptor, OX40 (TNFRSF4), which is expressed on the surface of activated T cells. The engagement of TNFSF4 with OX40 can modulate immune responses by enhancing the activity of T cells and potentially reducing the suppressive activity of regulatory T cells (Tregs), which can be important in the context of cancer immunotherapy. TNFSF4 has been implicated in antitumor immunity. Its interaction with OX40 on T cells can enhance T cell-mediated immunity against cancer cells. The signaling through OX40 induced by TNFSF4 can promote cell survival by inhibiting apoptosis and promoting cell proliferation, which is important for maintaining the T cell population during an immune response. TNFSF4 may also interact with other members of the TNF family and their receptors, potentially contributing to a complex network of signals that regulate immune cell function and homeostasis.

TNFSF4 Related Diseases

Abnormal expression or dysfunction of TNFSF4 has been associated with a variety of diseases, especially autoimmune diseases. For example, polymorphisms in the TNFSF4 gene have been linked to Sjogren's syndrome and systemic lupus erythematosus (SLE). In addition, the expression of TNFSF4 in breast cancer is also of interest to investigators because it may be involved in tumor immune escape and the regulation of anti-tumor immune responses. Overexpression of TNFSF4 was associated with shorter overall survival and disease-free survival, suggesting that it may play a role in tumor development and immune escape.

Bioapplications of TNFSF4

In cancer therapy, TNFSF4 is being investigated as a potential target for immune checkpoint inhibitors to enhance the immune response of T cells against tumors, particularly in the treatment of solid tumors such as breast cancer. In addition, agonist antibodies to TNFSF4 are being evaluated in clinical trials to determine whether they can promote the activation and proliferation of T cells, thereby enhancing the attack on tumors. In the field of cell therapy, the expression of TNFSF4 can enhance the effectiveness of treatments such as T cell therapy by promoting the persistence and function of T cells to improve the effectiveness of treatment for disease. In addition, the signaling pathway of TNFSF4 also shows a potential role in stem cell regulation and the control of cancer stem cells, which offers the possibility of developing new therapeutic approaches.