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].