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The HLA-B-21 dimorphism impacts on NK cell education and clinical outcome of immunotherapy in acute myeloid leukemia

Journal article
Authors Alexander Hallner
Elin Bernson
Brwa Ali Hussein
Frida Ewald Sander
Mats Brune
Johan Aurelius
Anna Martner
Kristoffer Hellstrand
Fredrik Bergh Thorén
Published in Blood
Volume 133
Issue 13
Pages 1479-1488
ISSN 0006-4971
Publication year 2019
Published at Sahlgrenska Cancer Center
Institute of Biomedicine, Department of Infectious Medicine
Pages 1479-1488
Language en
Links dx.doi.org/10.1182/blood-2018-09-87...
Keywords mhc class-i, natural-killer-cells, hla-c expression, inhibitory, receptors, activation, relapse, association, cd94/nkg2a, molecules, infection
Subject categories Hematology

Abstract

Natural killer (NK) cell function is regulated by inhibitory receptors, such as the family of killer immunoglobulin-like receptors (KIRs) and the NKG2A/CD94 heterodimer. These receptors recognize cognate HLA class I molecules on potential target cells, and recent studies imply that an HLA-B dimorphism at position -21 in the gene segment encoding the leader peptide dictates whether NK cell regulation primarily relies on the KIRs or the NKG2A/CD94 receptor. The impact of this HLA-B dimorphism on NK cell-mediated destruction of leukemic cells or on the course of leukemia is largely unknown. In a first part of this study, we compared functions of NK cells in subjects carrying HLA-B -21Mor 21T using interleukin-2 (IL-2)-activated NK cells and leukemic cells from patients with acute myeloid leukemia (AML). Subjects carrying HLA-B -21M harbored better-educated NKG2A1 NK cells and displayed superior capacity to degranulate lytic granules against KIR ligandmatched primary leukemic blasts. Second, we aimed to define the potential impact of HLA-B -21 variation on the course of AML in a phase 4 trial in which patients received IL-2based immunotherapy. In keeping with the hypothesis that 21M may be associated with improved NK cell functionality, we observed superior leukemia-free survival and overall survival in -21M patients than in -21T patients during IL-2based immunotherapy. We propose that genetic variation at HLA-B -21 may determine the antileukemic efficacy of activated NK cells and the clinical benefit of NK cell-activating immunotherapy.

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