Tumor cell ligands for NKG2D, DNAM-1, and NKp46

Tumor cell ligands for NKG2D, DNAM-1, and NKp46 represent a diverse group of surface proteins that act as critical recognition signals for the innate immune system. NKG2D ligands, including MICA, MICB, and the ULBP family (ULBP1-6), are MHC class I-related proteins typically upregulated in response to cellular stress, DNA damage, or oncogenic transformation (PMID: 21775010). DNAM-1 (CD226) ligands, such as CD155 (PVR) and CD112 (Nectin-2), belong to the nectin and nectin-like family and are frequently overexpressed in various solid and hematologic malignancies to facilitate NK cell-mediated lysis (PMID: 15039573). While NKp46 ligands on tumor cells are less clearly defined, they include certain heparan sulfate proteoglycans and stress-induced proteins like vimentin that trigger NK cell natural cytotoxicity (PMID: 10426993, PMID: 21616150). These ligands are essential for immune surveillance, as their engagement with activating receptors on NK cells and CD8+ T cells leads to the release of perforin and granzymes, resulting in tumor cell destruction. However, tumors often evade this response by proteolytically shedding these ligands (e.g., soluble MICA) or downregulating their expression to escape detection. Therapeutic approaches currently in development include monoclonal antibodies designed to stabilize these ligands on the cell surface, bispecific innate cell engagers (BiKEs), and CAR-NK cells that utilize these receptor-ligand interactions to enhance anti-tumor immunity.

Other names

NK cell activating receptor ligandsStress-induced ligandsNKG2DLDNAM-1LNKp46LMICA/BULBPsPVRNectin-2

Activation of NK cells and T cells through the engagement of activating receptors (NKG2D, DNAM-1, NKp46) to induce targeted lysis of ligand-expressing tumor cells.