A Defined Donor Activating Natural Killer Cell Receptor Phenotype Protects Against Leukemic Relapse after HLA-Identical Hematopoietic Stem Cell Transplantation.

Objective: Killer immunoglobulin-like receptors (KIRs) on Natural Killer (NK) cells recognize groups of HLA class I alleles. Failure to recognize the appropriate KIR ligand on a HLA class I-mismatched cell triggers NK cytotoxicity. Because KIR and HLA genes are located on different chromosomes matching for HLA does mostly not result in matched KIR genes in related HLA-identical hematopoietic stem cell transplantation (HSCT). Moreover, KIR genotypes are very diverse in the population and therefore we explored whether this KIR diversity could have any Graft-versus-Leukemia (GvL) effect in related, HLA-identical HSCT.

Methods: A total of 65 consecutive patients with leukemia (AML, CML, ALL) who received a first transplant at our institution, were included in the analysis. The median age of the patients was 34 years. The conditioning regimen included TBI + cytosine arabinoside + cyclophosphamide in the majority of the patients (85%). The source of stem cells was bone marrow (72%) or peripheral blood (28%). The NK KIR genotype (6 inhibiting and 5 activating KIRs) and molecular HLA compatibility (locus A, B, C, DRB1, DQB1, DPB1) were studied in all patients and their sibling donors.

Results and conclusion: Our analysis showed that the combined presence of the activating KIR receptors 2DS1 and 2DS2 on the donor NK cells is of major importance in protection against leukemic relapse in HLA-identical HSCT. In the patient group with a KIR2DS1(+)2DS2(+) donor, relapse was significantly lower (2/15; 13%) compared to all other donors (23/50; 46%) (P=0.01). Additionally, we found a direct relationship between the number of HLA class I - activating KIR interactions and relapse. The more activating KIR receptor-HLA-C ligand interactions possible, the less relapse observed (P=0.05). However, we cannot exclude at this moment that a hitherto unknown ligand (such as a viral protein or a tumor associated or -specific protein) could substitute for a HLA class I antigen. HLA class I down-regulation is frequently observed on leukemic cells and decreases the interaction with inhibitory NK receptors. The presence of sufficient donor activating NK receptors to overcome the remaining inhibition is likely the mechanism that mediates the elimination of residual leukemic cells.