KIR3DL1/HLA-B subtypes govern acute myelogenous leukemia relapse after hematopoietic cell transplantation Journal Article


Authors: Boudreau, J. E.; Giglio, F.; Gooley, T. A.; Stevenson, P. A.; Le Luduec, J. B.; Shaffer, B. C.; Rajalingam, R.; Hou, L.; Hurley, C. K.; Noreen, H.; Reed, E. F.; Yu, N.; Vierra-Green, C.; Haagenson, M.; Malkki, M.; Petersdorf, E. W.; Spellman, S.; Hsu, K. C.
Article Title: KIR3DL1/HLA-B subtypes govern acute myelogenous leukemia relapse after hematopoietic cell transplantation
Abstract: PurposeDisease 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 cellsupregulated in the post-HCT environmentsignals 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 MethodsBy 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.ResultsSegregated 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.ConclusionConsideration 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.
Keywords: transplantation; education; donor selection; polymorphism; mhc class-i; inhibitory receptors; hla-b; unrelated; nk cells; receptor gene diversity; kir-ligands
Journal Title: Journal of Clinical Oncology
Volume: 35
Issue: 20
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2017-07-10
Start Page: 2268
End Page: 2278
Language: English
ACCESSION: WOS:000404985200009
DOI: 10.1200/jco.2016.70.7059
PROVIDER: wos
PMCID: PMC5501362
PUBMED: 28520526
Notes: Article -- Source: Wos
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MSK Authors
  1. Katharine C Hsu
    131 Hsu
  2. Fabio Giglio
    3 Giglio
  3. Brian Carl Shaffer
    40 Shaffer