Tumor cell surface ligands for natural cytotoxicity receptors (NCRs)

Tumor cell surface ligands for natural cytotoxicity receptors (NCRs) refer to a diverse set of molecules, primarily B7-H6, expressed selectively on transformed cells that engage activating NCRs (NKp30, NKp44, NKp46) on natural killer (NK) cells to trigger tumor cell lysis and cytokine production. B7-H6, a B7 family homolog with V-like and C-like Ig domains, binds NKp30 in an antibody-like manner using CDR-like loops, forming a 1:1 complex that spans ~100 Å and promotes NK cell immune synapse formation. This interaction lacks expression on healthy cells, acting as an "induced self" signal of cellular stress or transformation, distinct from MHC-related ligands for other NK receptors like NKG2D. In cancer, these ligands contribute to NK surveillance against diverse tumors including leukemias, carcinomas, and neuroblastomas, though their full spectrum (including BAT3, viral pp65) suggests multifaceted NK activation. Therapeutically, no drugs directly target these ligands yet, but structural insights support developing NKp30 agonists or bispecifics to boost antitumor immunity, potentially synergizing with NKG2D pathways while risking excessive inflammation.

Other names

B7-H6BAT3pp65 (CMV tegument protein)heparan sulfate/heparin moleculesPfEMP-1 (Plasmodium falciparum erythrocyte membrane protein-1)

None (no drugs; hypothetical: soluble B7-H6 or NKp30 variants to enhance NK cytolytic activity or ADCC against B7-H6+ tumors)