DNAX Accessory Molecule-1 (DNAM-1) is a transmembrane protein and a major activating receptor in the body’s defense system. Also known as CD226, DNAM-1 is a member of the immunoglobulin superfamily designed to receive distress signals from other cells. This molecule alerts the immune system to the presence of threatening cells, such as those that are infected or transformed. Its expression is necessary for several immune cell types to mount a coordinated defense.
Identifying the Targets
DNAM-1 is a 65 kilodalton glycoprotein displayed on the surface of several immune cell populations. Structurally, it consists of a short intracellular tail, a transmembrane segment, and two extracellular immunoglobulin-like domains that are responsible for binding its target molecules. DNAM-1 is constitutively expressed on Natural Killer (NK) cells and various T cells, which serve as the primary effectors of immune surveillance.
NK cells are part of the innate immune system, capable of rapid destruction of target cells. T cells, particularly cytotoxic CD8+ T cells, belong to the adaptive immune system and provide a specific, memory-driven response. DNAM-1’s presence on both innate and adaptive immune cells provides a unified mechanism for recognizing and reacting to cellular danger.
The Immune System’s Alarm Bell
DNAM-1 acts as a sensor for cellular distress by recognizing specific stress ligands. The two primary molecules DNAM-1 binds to are PVR (poliovirus receptor, CD155) and Nectin-2 (CD112). These ligands are normally expressed at low levels on healthy cells, but their presence increases significantly when a cell is under stress, such as during viral infection or oncogenic transformation.
When DNAM-1 encounters these upregulated ligands, it initiates a signal transduction cascade. This process begins when the intracellular tail of DNAM-1 is phosphorylated by specialized enzymes, such as Src family kinases. This phosphorylation creates a docking site for adaptor proteins like Grb2.
Grb2 binding triggers a downstream pathway involving the activation of enzymes such as Vav-1 and phospholipase C-γ1 (PLC-γ1). This relay causes an increase in intracellular calcium and promotes actin polymerization, necessary for the immune cell to physically connect with the target cell. The signaling outcome is the activation of the immune cell’s killing machinery, leading to the release of cytotoxic granules and pro-inflammatory messengers like interferon-gamma. This activation is balanced by inhibitory receptors, such as TIGIT and CD96, which compete with DNAM-1 for binding to PVR and Nectin-2.
DNAM-1’s Role in Cancer Surveillance
The mechanism of DNAM-1 activation is directly applied to cancer surveillance, the body’s ability to detect and destroy malignant cells. When a tumor cell undergoes uncontrolled growth, the resulting cellular stress often causes it to overexpress the DNAM-1 ligands, PVR and Nectin-2. This high density of ligands marks the tumor cell as a target for destruction by NK and T cells expressing DNAM-1.
DNAM-1 signaling drives the initial recognition and subsequent elimination of early malignant cells, serving as an important protective layer against tumor development. Preclinical evidence shows that DNAM-1 deficiency can lead to increased tumor formation and faster disease progression. The molecule is particularly significant for tumors that might not display other common danger signals, extending the breadth of the immune system’s surveillance capabilities.
Advanced tumors often evade this DNAM-1-mediated attack. A common tactic is the counter-expression of inhibitory receptors, such as TIGIT, which bind PVR and Nectin-2 but deliver a “stop” signal. Tumors may also downregulate PVR and Nectin-2 expression, reducing their visibility to immune cells.
Therapeutic Applications
The anti-tumor activity driven by DNAM-1 has made its pathway a major focus for the development of new cancer immunotherapies. One strategy involves targeting inhibitory receptors that compete with DNAM-1, such as TIGIT. Using monoclonal antibodies to block TIGIT removes the inhibitory brake on the immune system, thereby tipping the balance in favor of the activating signal from DNAM-1.
Another approach involves genetically engineering immune cells to enhance the DNAM-1 pathway. This includes creating chimeric antigen receptor (CAR) T cells and NK cells that incorporate a highly active form of the DNAM-1 receptor. These engineered cells recognize PVR and Nectin-2 ligands with increased affinity, ensuring a robust activation signal that overrides tumor inhibitory mechanisms. This strategy is being investigated in clinical trials for treating both solid and blood cancers.
DNAM-1-based therapies target ligands widely overexpressed across many cancer types, suggesting broad applicability. By restoring or amplifying the body’s natural alarm system, these therapeutic interventions aim to unleash a powerful and specific immune response against malignant cells.