KIR and HLA Genotypes Predictive of Low-Affinity Interactions Are Associated with Lower Relapse in Autologous Hematopoietic Cell Transplantation for Acute Myeloid Leukemia

Abstract

Killer cell Ig–like receptors (KIRs) bind cognate HLA class I ligands with distinct affinities, affecting NK cell licensing and inhibition. We hypothesized that differences in KIR and HLA class I genotypes predictive of varying degrees of receptor–ligand binding affinities influence clinical outcomes in autologous hematopoietic cell transplantation (AHCT) for acute myeloid leukemia (AML). Using genomic DNA from a homogeneous cohort of 125 AML patients treated with AHCT, we performed KIR and HLA class I genotyping and found that patients with a compound KIR3DL1+ and HLA-Bw4-80Thr+, HLA-Bw4-80Ile– genotype, predictive of low-affinity interactions, had a low incidence of relapse, compared with patients with a KIR3DL1+ and HLA-Bw4-80Ile+ genotype, predictive of high-affinity interactions (hazard ratio [HR], 0.22; 95% confidence interval [CI], 0.06–0.78; p = 0.02). This effect was influenced by HLA-Bw4 copy number, such that relapse progressively increased with one copy of HLA-Bw4-80Ile (HR, 1.6; 95% CI, 0.84–3.1; p = 0.15) to two to three copies (HR, 3.0; 95% CI, 1.4–6.5; p = 0.005) and progressively decreased with one to two copies of HLA-Bw4-80Thr (p = 0.13). Among KIR3DL1+ and HLA-Bw4-80Ile+ patients, a predicted low-affinity KIR2DL2/3+ and HLA-C1/C1 genotype was associated with lower relapse than a predicted high-affinity KIR2DL1+ and HLA-C2/C2 genotype (HR, 0.25; 95% CI, 0.09–0.73; p = 0.01). Similarly, a KIR3DL1+ and HLA-Bw4-80Thr+, HLA-Bw4-80Ile– genotype, or lack of KIR3DL1+ and HLA-Bw4-80Ile+ genotype, rescued KIR2DL1+ and HLA-C2/C2 patients from high relapse (p = 0.007). These findings support a role for NK cell graft-versus-leukemia activity modulated by NK cell receptor–ligand affinities in AHCT for AML.