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

被引:48
|
作者
Hallner, Alexander [1 ]
Bernson, Elin [1 ]
Hussein, Brwa Ali [1 ]
Sander, Frida Ewald [1 ]
Brune, Mats [2 ]
Aurelius, Johan [1 ]
Martner, Anna [1 ]
Hellstrand, Kristoffer [1 ]
Thoren, Fredrik B. [1 ]
机构
[1] Univ Gothenburg, Sahlgrenska Canc Ctr, TIMM Lab, Gothenburg, Sweden
[2] Univ Gothenburg, Dept Hematol, Gothenburg, Sweden
基金
瑞典研究理事会;
关键词
MHC CLASS-I; NATURAL-KILLER-CELLS; HLA-C EXPRESSION; INHIBITORY RECEPTORS; ACTIVATION; RELAPSE; ASSOCIATION; CD94/NKG2A; MOLECULES; INFECTION;
D O I
10.1182/blood-2018-09-874990
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:1479 / 1488
页数:10
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