DNAM-1 ligands (Poliovirus receptor and Nectin-2) (CD155 and CD112)

DNAM-1 ligands, primarily Poliovirus receptor (CD155) and Nectin-2 (CD112), are cell surface glycoproteins that play a critical role in the regulation of immune responses [11, 12]. These ligands are members of the nectin and nectin-like family and are frequently overexpressed on leukemia cells, particularly in acute myeloid leukemia (AML) [4, 7]. They interact with the activating receptor DNAM-1 (CD226) on natural killer (NK) cells and T cells to promote anti-tumor cytotoxicity [13, 14]. However, they also bind to inhibitory receptors such as TIGIT, CD96, and PVRIG, which can lead to immune evasion by the tumor [10, 25]. In leukemia, high expression of these ligands is often associated with poor prognosis and reduced immune surveillance [1, 4]. Therapeutic strategies targeting this axis include the use of TIGIT-blocking antibodies to prevent inhibitory signaling and the use of small molecule inhibitors like FLT3 inhibitors that can modulate ligand expression [1, 18]. Additionally, novel approaches such as CD155-targeted CAR-T cells and anti-CD155 antibodies are being explored to directly target these molecules on leukemic blasts [22, 31].

Other names

Poliovirus receptor (PVR)Nectin-2Nectin-like protein 5 (Necl-5)CD155CD112Poliovirus receptor-related 2 (PVRL2)Herpesvirus entry mediator B (HVEB)Poliovirus receptor-related protein 2 (PRR2)DNAM-1 ligands (DNAM-1L)

Drugs targeting the DNAM-1 ligand axis work by either downregulating the expression of CD155 and CD112 on leukemia cells (e.g., FLT3 inhibitors) or by blocking their interaction with inhibitory receptors like TIGIT and PVRIG (e.g., monoclonal antibodies) [1, 18, 24]. By preventing inhibitory signaling, these agents restore the dominance of the activating DNAM-1 receptor, thereby enhancing the cytotoxic activity of NK cells and T cells against the tumor [4, 7, 10].