3.7 TNFRSF25 (Death Receptor 3, DR3)
TNFRSF25, or Death Receptor 3 (DR-3, also known as TRAMP, LARD and WSL-1 ), is a member of the tumor necrosis factor receptor superfamily expressed on various immune cells, including T cells and natural killer (NK) cells [351, 352]. Its ligand, TNF-like ligand 1A (TL1A or TNFSF15), is primarily expressed on antigen-presenting cells (APCs) and endothelial cells. The interaction between TNFRSF25 and TL1A plays a critical role in regulating immune responses, particularly in modulating T cell and NK cell functions [351, 352].
When TNFRSF25 engages with TL1A, it triggers intracellular signaling pathways that enhance immune cell activation and effector functions. This includes promoting T cell proliferation, survival, and cytokine production, such as interleukin-2 (IL-2), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α). These cytokines are essential for mounting effective immune responses against infections and tumors [353, 354].
In the context of cancer immunotherapy, TNFRSF25 has emerged as a potential therapeutic target [355]. Agonistic antibodies or other agents that activate TNFRSF25 are being investigated in preclinical studies [356]. These TNFRSF25 agonists aim to enhance anti-tumor immune responses by boosting the cytotoxic activity of T cells and NK cells against cancer cells. A study by et al. demonstrated that TNFRSF25 agonists (soluble TL1A) in mouse plasmacytomas lead to the elimination of tumor cells in a CD8(+) T-cell-dependent manner and render mice immune to subsequent tumor cell challenges. They proposed that TNFRSF25 agonists like soluble TL1A could potentially be used to enhance the immunogenicity of vaccines designed to elicit human anti-tumor CD8(+) T cells [357].