NK Cell Education in Tumor Immune Surveillance: DNAM-1/KIR Receptor Ratios as Predictive Biomarkers for Solid Tumor Outcome

Natural killer cell (NKc)-based therapies offer promising outcomes in patients with tumors, but they could improve with appropriate selection of donors and optimization of methods to expand NKcs in vitro Education through licensing interactions of inhibitory killer cell immunoglobulin-like receptors (iKIR) and NKG2A with their cognate HLA class-I ligands optimizes NKc functional competence. This work has evaluated the role of licensing interactions in NKc differentiation and the survival of cancer patients. We have analyzed KIR and KIR-ligand genes, and the expression of activating (CD16 and DNAM-1/CD226) and inhibitory (NKG2A and iKIRs) receptors on peripheral blood NKcs in 621 healthy controls and 249 solid cancer patients (80 melanoma, 80 bladder, and 89 ovarian). Licensing interactions upregulated the expression of activating CD226, reduced that of iKIR receptors, and shifted the CD226/iKIR receptor ratio on NKc membranes to activating receptors. A high tumor burden decreased CD226 expression, reduced the ratio of CD226/iKIR, and negatively affected patient survival. The progression-free survival (38.1 vs. 67.0 months, P < 0.002) and overall survival (56.3 vs. 99.6 months, P < 0.00001) were significantly shorter in patients with lower expression of CD226 on NKcs. Hence, transformed cells can downmodulate these licensing-driven receptor rearrangements as a specific mechanism to escape NKc immune surveillance. Our results suggest the importance of the CD226/iKIR receptor ratio of NKcs induced by licensing interactions as critical determinants for solid cancer immune surveillance, and may provide predictive biomarkers for patient survival that may also improve the selection of donors for NKc immunotherapy.