title: 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.
authors: Department of Medicine, University of California, San Francisco, San Francisco, CA 94143; and.
authors: John
authors: J
authors: Marra
authors: Department of Medicine, University of California, San Francisco, San Francisco, CA 94143; and.
authors: Justin
authors: J
authors: Greene
authors: Biostatistics Core, University of California, San Francisco, Helen Diller Comprehensive Cancer Center, San Francisco, CA 94115.
authors: Jimmy
authors: J
authors: Hwang
authors: Department of Medicine, University of California, San Francisco, San Francisco, CA 94143; and.
authors: Juan
authors: J
authors: Du
authors: Department of Medicine, University of California, San Francisco, San Francisco, CA 94143; and.
authors: Lloyd
authors: L
authors: Damon
authors: Department of Medicine, University of California, San Francisco, San Francisco, CA 94143; and.
authors: Tom
authors: T
authors: Martin
authors: Department of Medicine, University of California, San Francisco, San Francisco, CA 94143; and venstromj@gmail.com.
authors: Jeffrey M
authors: JM
authors: Venstrom
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D005838:Genotype; D020544:Graft vs Leukemia Effect / Q000235:genetics / Q000276:immunology*; D015235:HLA-B Antigens / Q000235:genetics* / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D008875:Middle Aged; D054340:Receptors, KIR / Q000235:genetics* / Q000276:immunology; D012008:Recurrence; D012189:Retrospective Studies; D014184:Transplantation, Homologous; D055815:Young Adult
chemical_list: D015235:HLA-B Antigens; D054340:Receptors, KIR