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

Alexander Hallner, Elin Bernson, Brwa Ali Hussein, Frida Ewald Sander, Mats Brune, Johan Aurelius, Anna Martner, Kristoffer Hellstrand and Fredrik B. Thorén

Key points

  • -21M individuals harbor better-educated NKG2A+ NK cells with superior degranulation capacity.

  • HLA-B dimorphism were associated with improved outcome in -21M patients during IL-2 based immunotherapy.


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 mainly relies on the KIRs or the NKG2A/CD94 receptor. The impact of this HLA-B dimorphism for NK cell-mediated destruction of leukemic cells or for 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 -21M or 21T using IL 2-activated NK cells and leukemic cells from patients with acute myeloid leukemia (AML). Subjects carrying HLA-B -21M harbored better-educated NKG2A+ NK cells and displayed superior capacity to degranulate lytic granules against KIR ligand-matched primary leukemic blasts. Secondly, we aimed to define the potential impact of HLA-B -21 variation for the course of AML in a phase IV trial where patients received IL 2-based immunotherapy. In keeping with the hypothesis that 21 M may be associated with improved NK cell functionality, we observed superior leukemia-free survival and overall survival in -21M than in -21T patients during IL 2-based immunotherapy. We propose that genetic variation at HLA-B -21 may determine the anti-leukemic efficacy of activated NK cells and the clinical benefit of NK cell-activating immunotherapy.

  • Submitted September 13, 2018.
  • Accepted December 31, 2018.