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), that is, 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.
Highlights
Acute myeloid leukemia (AML) is a genetically and morphologically heterogeneous disease characterized by the expansion and accumulation of immature myeloid cells in the bone marrow and peripheral blood
We aimed to clarify whether the relapse risk of AML patients receiving HDC/IL-2 immunotherapy was affected by their killer-immunoglobulin-like receptors (KIRs)/HLA genotypes
Previous reports from the Re:Mission trial and other studies have identified a population of patients with intact natural cytotoxicity receptor (NCR) expression with superior prognosis over patients with NCR expression deficiency.[5,32,33,43]
Summary
Acute myeloid leukemia (AML) is a genetically and morphologically heterogeneous disease characterized by the expansion and accumulation of immature myeloid cells in the bone marrow and peripheral blood. The prognosis is determined by risk factors such as chromosomal abnormalities, gene mutations and age, and based on these and other factors AML can be classified into high-, intermediate- or low-risk disease. Depending on the risk category, between 65 to as low as 5% of patients experience long-term survival.[1] Despite achieving complete remission (CR) in response to chemotherapy, alone or combined with autologous stem cell transplantation, the vast majority of intermediate and high-risk AML patients are not cured as a small residual clone of leukemic cells may expand to cause relapse with poor prospects of longterm survival.[2] To prevent relapse, younger patients may receive an allogeneic stem cell transplant (allo-SCT), but not all patients are eligible for transplantation and additional strategies to avoid relapse in non-transplanted patients are highly warranted.[3]. There are two main KIR haplotypes; the A haplotype that comprises genes for iKIRs and KIR2DS4, and the B haplotype that in addition to iKIR genes carries genes for a variable set of up to 6 activating KIRs (aKIRs).[10,11,12] The ligands for aKIRs are not completely characterized, but KIR2DS1 recognizes HLA-C2, and KIR2DS2 recognizes HLA-A11 and HLA-C1.13–17
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