KIR3DL1/HLA-B Subtypes Govern Acute Myelogenous Leukemia Relapse After Hematopoietic Cell Transplantation

Abstract

Purpose Disease relapse remains a major challenge to successful outcomes in patients who undergo allogeneic hematopoietic cell transplantation (HCT). Donor natural killer (NK) cell alloreactivity in HCT can control leukemic relapse, but capturing alloreactivity in HLA-matched HCT has been elusive. HLA expression on leukemia cells-upregulated in the post-HCT environment-signals for NK cell inhibition via inhibitory killer immunoglobulin-like (KIR) receptors and interrupts their antitumor activity. We hypothesized that varied strengths of inhibition among subtypes of the ubiquitous KIR3DL1 and its cognate ligand, HLA-B, would titrate NK reactivity against acute myelogenous leukemia (AML). Patients and Methods By using an algorithm that was based on polymorphism-driven expression levels and specificities, we predicted and tested inhibitory and cytotoxic NK potential on the basis of KIR3DL1/HLA-B subtype combinations in vitro and evaluated their impact in 1,328 patients with AML who underwent HCT from 9/10 or 10/10 HLA-matched unrelated donors. Results Segregated by KIR3DL1 subtype, NK cells demonstrated reproducible patterns of strong, weak, or noninhibition by target cells with defined HLA-B subtypes, which translated into discrete cytotoxic hierarchies against AML. In patients, KIR3DL1 and HLA-B subtype combinations that were predictive of weak inhibition or noninhibition were associated with significantly lower relapse (hazard ratio [HR], 0.72; P = .004) and overall mortality (HR, 0.84; P = .030) compared with strong inhibition combinations. The greatest effects were evident in the high-risk group of patients with all KIR ligands (relapse: HR, 0.54; P < .001; and mortality: HR, 0.74; P < .008). Beneficial effects of weak and noninhibiting KIR3DL1 and HLA-B subtype combinations were separate from and additive to the benefit of donor activating KIR2DS1. Conclusion Consideration of KIR3DL1-mediated inhibition in donor selection for HLA-matched HCT may achieve superior graft versus leukemia effects, lower risk for relapse, and an increase in survival among patients with AML.

KIR3DL1 and HLA-B Density and Binding Calibrate NK Education and Response to HIV

“…KIR3DS1 + NK cells were non-responsive to 721.221 target cells, irrespective of donor HLA-B background, confirming that this population is not educated by HLA-B (Supplementary Figure 1A). Finally, NK cells exhibiting KIR3DL1-n were educated by both Bw4-80I and -80T for an intermediate level of responsiveness (Supplementary Figure 1B), consistent with previous conclusions that the receptors’ intracellular retention does not preclude education (45, 46) (Submitted for publication).…”

“…Members of the “null” group (KIR3DL1-n), most commonly KIR3DL1*004 and *019 , are not expressed on the cell surface under homeostatic conditions (44) and therefore cannot be detected by staining with either of the anti-KIR3DL1 antibodies, DX9 or Z27. KIR3DL1-n can, however, be stained intracellularly with clone 177407 or on the cell surface after overnight culture at 25°C (45, 46). The activating KIR3DS1 subtypes are weakly detected on NK surfaces by Z27 and are not bound at all by DX9 (18).…”

Vorinostat plus tacrolimus/methotrexate to prevent GVHD after myeloablative conditioning, unrelated donor HCT

“…27 We recorded a relapse incidence of 19% (95% CI, 9%-36%) at 1 year in a cohort with predominantly AML/MDS diagnosis (95%), which is commensurate with the 20% to 40% reported in a recent registry study examining AML relapse after URD HCT. 28 Together, the low incidence of relapse and acute GVHD observed in this trial yielded an NRM of 16% (95% CI, 7%-34%) and an overall survival of 76% (95% CI, 63%-92%) at 1 year. These data compare favorably with the large study of 1328 patients with AML who received URD allografts in which 1-year OS ranged between 40% and 50%.…”

“…These data compare favorably with the large study of 1328 patients with AML who received URD allografts in which 1-year OS ranged between 40% and 50%. 28 We also examined GRFS, which compared favorably with an incidence of 47% (95% CI, 32%-69%) at 1 year. Holtan et al recently reported a 1-year GRFS of 28% (95% CI, 17%-39%) after URD HCT.…”

The immunogenetics of neurological disease

“…Although a huge number of unique haplotypes are described, a few comparatively common haplotypes repeatedly account for greater than 90% of the KIR haplotypic variation detected within a specific population, and are observed throughout major ethnic groups. 166,167 Our recent work and that of others has shown that the prevalence of KIR haplotypes and specific combinations of cognate KIR and HLA allotypes are associated in autoimmune 162,[168][169][170] and infectious diseases such as human immunodeficiency virus (HIV) and hepatitis C, [171][172][173][174] cancer, 175,176 and are critical to the success of solid organ and haematopoietic stem cell transplant (HCT) [177][178][179][180] and pregnancy. [181][182][183][184][185] Although the correlation of HLA variation with neurological disease has been well documented, there is a paucity of studies aiming to evaluate the impact of NK cells or their receptors, including KIR in these diseases.…”