DNAX accessory molecule-1 ligands and Natural Killer cell activating ligands (DNAM-1L)

DNAX accessory molecule-1 (DNAM-1) ligands, primarily CD155 (PVR) and CD112 (Nectin-2), are critical mediators of immune surveillance by Natural Killer (NK) cells and T cells (UniProt P15151, Q92692). These ligands are members of the immunoglobulin superfamily and are frequently overexpressed on the surface of various tumor cells, including melanoma, lung cancer, and colorectal cancer (PubMed 29305462). While DNAM-1 provides a potent activating signal upon binding these ligands, the same ligands also bind to inhibitory receptors such as TIGIT and PVRIG (CD112R), which often dominate in the tumor microenvironment to suppress anti-tumor immunity (PMC6169832). Consequently, the DNAM-1/TIGIT/PVRIG axis has emerged as a significant checkpoint system similar to the PD-1/PD-L1 pathway. Therapeutic strategies involve using monoclonal antibodies to block the inhibitory interactions or promote DNAM-1-mediated activation, thereby restoring the cytotoxic activity of NK and CD8+ T cells against tumor cells (Nature Reviews Drug Discovery, 2020). Other NK/tumor ligands, such as MICA/B and ULBPs, follow a similar paradigm of being upregulated under cellular stress or malignancy to trigger immune recognition via the NKG2D receptor (PMC3661172).

Other names

CD155PVRPoliovirus receptorCD112Nectin-2PVRL2NKG2D ligandsMICAMICBULBP

Blockade of inhibitory receptor binding (TIGIT/PVRIG) to ligands (CD155/CD112) to restore DNAM-1-mediated activating signals and enhance NK/T-cell antitumor effector functions.