Recipient expression of ligands for donor inhibitory KIRs enhances NK‐cell function to control leukemic relapse after haploidentical transplantation

Natural killer (NK) cells that express self‐HLA‐specific receptors (where HLA is human leukocyte antigen) are “licensed” and more readily activated than unlicensed cells; therefore, NK‐cell licensing could influence the antileukemia effects of NK cells following haploidentical stem cell transplantation (haplo‐SCT). In this study, we compared the functionality of reconstituting NK cells, based on CD107α expression and interferon‐γsecretion, in a cohort of 29 patients that expressed ( n = 8) or lacked ( n = 21) class I human leukocyte antigens for donor inhibitory killer cell immunoglobulin‐like receptors (KIRs) following T‐cell‐replete haplo‐SCT. We also addressed whether recipient expression of class I ligands for donor inhibitory KIRs could predict relapse occurrence in another cohort of 188 patients. A longitudinal analysis indicated that patients presenting class I for all donor inhibitory KIRs showed more capable functional NK effector cells when tested against class I negative K562 cells and primary leukemic cells within 3 months of transplantation. The lowest 7‐year relapse incidence was observed when donor KIRs were ligated by recipient class I ( n = 60) compared with donor–host partnerships where donor KIR + cells were ligated by donor, but not recipient class I ( n = 86, p = 0.026) or KIRs that were ligated by neither donor nor recipient class I ( n = 42, p = 0.043). This study suggests that haplo‐SCT recipients presenting class I for donor inhibitory KIRs promote NK‐cell licensing, leading to decreased relapse rates.