Tumor cell surface ligands recognized by NK cell activating receptors and T-cell receptors

Tumor cell surface ligands recognized by NK cell activating receptors and T-cell receptors represent a diverse array of molecules that act as 'danger signals' to alert the immune system to malignant transformation. This group primarily includes stress-induced ligands such as MHC class I polypeptide-related sequences A and B (MICA/B) and UL16-binding proteins (ULBPs), which are recognized by the NKG2D receptor on Natural Killer (NK) cells and cytotoxic T cells (Duan et al., 2019, Frontiers in Immunology). Other significant ligands include B7-H6, which triggers the natural cytotoxicity receptor NKp30, and PVR (CD155), which activates the DNAM-1 receptor (Brandt et al., 2009, Journal of Experimental Medicine). While these ligands are minimally expressed on healthy cells, they are frequently upregulated in various cancers due to genomic instability, DNA damage, or oncogenic signaling, facilitating immune-mediated tumor clearance. Therapeutic strategies targeting these ligands include CAR-T and CAR-NK cells (e.g., CYAD-01) and monoclonal antibodies (e.g., 7C6) designed to prevent the proteolytic shedding of MICA/B, a common immune evasion mechanism where tumors release soluble ligands to desensitize immune cells (Groh et al., 2002, Nature).

Other names

NKG2D ligandsStress-induced ligandsNK cell activating ligandsTumor-associated antigensMIC/ULBP proteinsNCR ligands

Activation of NK cell and T-cell mediated cytotoxicity through direct binding of surface ligands or prevention of proteolytic ligand shedding to maintain tumor visibility.