The impact of KIR and HLA in AML immunotherapy - a Swedish study

Natural Killer (NK) cells are regulated by interactions between Killer-Immunoglobulin-Like Receptors (KIRs) and their corresponding Human Leukocyte Antigen (HLA) ligands. KIRs can be grouped into either inhibitory (KIR A) or activating and inhibitory receptors (KIR B). However, a significant amount of individuals lack ligands for inhibitory KIRs, thus have missing ligands, which can give rise to autoreactive unlicensed NK cells.

In an article published ahead of print in Leukemia on 22^nd May 2017, Elin Bernson, from the University of Gothenburg, and colleagues investigated the impact of KIR/HLA genotypes on the relapse risk of Acute Myeloid Leukemia (AML) patients receiving  low-dose Interleukin 2 (IL-2) in combination with Histamine Dihydrochloride (HDC/IL-2) in a phase IV study (NCT01347996).¹ Previous findings from this phase IV study have shown that HDC/IL-2 administration in AML patients can lead to an up-regulation of Natural Cytotoxicity Receptors (NCRs [activating receptors of NK cells and includes NKp46]) on NK cells. Furthermore, high frequency of NKp46 significantly improved Leukemia Free Survival (LFS) and Overall Survival (OS).²

In this current study, NK cell phenotypes and KIR/HLA genotypes were determined in blood samples from eighty-one AML patients before and after the first and third cycles of HDC/IL-2. ¹

The key results of the study were:

• High expression of NKp46 was associated with a clinical benefit in patients with a missing ligand only and not in patients with all ligands present
• High expression of NKp46 was associated with a clinical benefit in patients with KIR B/x genotype and not in patients with KIR A/A genotype
• Improved LFS was associated with high frequency of unlicensed NKG2A^- NS-KIR NK cells before the start of treatment (P = 0.06) and before the third treatment cycle (P = 0.05)
• High expression of NKp46 was associated with a clinical benefit in patients (n = 30) with high frequency of unlicensed NKG2A^- NS-KIR NK cells; P < 0.0001

In summary, high NKp46 expression and high frequency of unlicensed NK cells are associated with improved survival outcomes. Thus suggesting that they may “constitute an anti-leukemic effector population of relevance to the clinical outcome of HDC/IL2 immunotherapy in AML”.

The authors concluded by suggesting that their results support that “unlicensed, functional NK cells are relevant to prognosis in AML” and “strategies to unleash the cytotoxicity of unlicensed NK cells should be considered in anti-leukemic immunotherapy”.

Abstract

Interactions between killer-immunoglobulin-like receptors (KIRs) and their HLA class I ligands are instrumental in natural killer (NK) cell regulation and protect normal tissue from NK cell attack. Human KIR haplotypes comprise genes encoding mainly inhibitory receptors (KIR A) or activating and inhibitory receptors (KIR B). A substantial fraction of humans lack ligands for inhibitory KIRs (iKIRs), i.e. a ‘missing ligand’ genotype. KIR B/x and missing ligand genotypes may thus give rise to potentially autoreactive, unlicensed NK cells. Little is known regarding the impact of such genotypes in untransplanted acute myeloid leukemia (AML). For this study, NK cell phenotypes and KIR/HLA genotypes were determined in 81 AML patients who received immunotherapy with histamine dihydrochloride and low-dose IL-2 for relapse prevention (NCT01347996). We observed that presence of unlicensed NK cells impacted favorably on clinical outcome, in particular among patients harboring functional NK cells reflected by high expression of the natural cytotoxicity receptor (NCR) NKp46. Genotype analyses suggested that the clinical benefit of high NCR expression was restricted to patients with a missing ligand genotype and/or a KIR B/x genotype. These data imply that functional NK cells are significant anti-leukemic effector cells in patients with KIR/HLA genotypes that favor NK cell autoreactivity.