Endogenous Natural Killer cell ligands (NK cell ligands)

Endogenous Natural Killer (NK) cell ligands are a heterogeneous group of cell-surface proteins expressed by tumor cells that modulate NK cell activity through interaction with various activating and inhibitory receptors. Activating ligands, such as MHC class I polypeptide-related sequence A and B (MICA/B) and UL16-binding proteins (ULBPs), typically signal cellular stress and trigger NK cell-mediated cytotoxicity via the NKG2D receptor (PMID: 21739679). Conversely, inhibitory ligands, including classical MHC class I molecules and non-classical HLA-E, bind to Killer-cell Immunoglobulin-like Receptors (KIRs) and NKG2A, respectively, to provide "self" recognition and prevent autoimmunity (PMID: 30503213). In cancer, tumor cells frequently employ "immunoediting" to downregulate activating ligands or upregulate inhibitory ones, thereby evading immune detection. Additionally, the proteolytic shedding of activating ligands by enzymes like ADAM10 and ADAM17 results in soluble forms that act as decoys, further suppressing the immune response (PMID: 18424730). Therapeutic interventions aim to restore NK cell surveillance by blocking inhibitory checkpoints (e.g., using Monalizumab), preventing ligand shedding, or pharmacologically inducing the expression of activating ligands on the tumor surface.

Other names

NKG2D ligandsNK cell activating ligandsNK cell inhibitory ligandsTumor-associated NK ligandsStress-induced ligands

Blockade of inhibitory ligand-receptor interactions, upregulation of activating ligand expression, and prevention of ligand shedding from the cell surface.