Tumor ligands for Natural Killer cell activating and inhibitory receptors (NK cell ligands)

Tumor ligands for Natural Killer (NK) cell activating and inhibitory receptors represent a heterogeneous group of surface molecules that dictate the immune system's ability to recognize and destroy malignant cells. Activating ligands, such as MHC class I polypeptide-related sequence A and B (MICA/B) and UL16-binding proteins (ULBPs), are often upregulated in response to cellular stress and bind to the NKG2D receptor to stimulate NK cell cytotoxicity (PubMed: 29371644). In contrast, inhibitory ligands like HLA-E and classical MHC class I molecules bind to receptors such as NKG2A and Killer-cell Immunoglobulin-like Receptors (KIRs), respectively, to deliver "off" signals that prevent NK cells from attacking healthy or "self" cells (PubMed: 30510241). Tumors frequently exploit this system by downregulating activating ligands or overexpressing inhibitory ones, such as CD155 (PVR), which binds the inhibitory receptor TIGIT (PubMed: 31435035). Therapeutic interventions, including monoclonal antibodies like Monalizumab (targeting the NKG2A/HLA-E axis) and Lirilumab (targeting KIRs), aim to disrupt these inhibitory checkpoints to unleash NK cell anti-tumor activity (PubMed: 28103134). Additionally, bispecific and trispecific NK cell engagers (BiKEs and TriKEs) are being developed to bridge NK cells directly to tumor ligands, bypassing traditional evasion mechanisms (PubMed: 31209019).

Other names

NK cell receptor ligandsTumor-associated NK ligandsNKG2D ligandsNKG2A ligandsKIR ligandsNatural Killer cell ligands

Inhibition of inhibitory receptor-ligand interactions (checkpoint blockade) or potentiation of activating receptor-ligand interactions to enhance NK cell-mediated tumor lysis.