Impact of killer-immunoglobulin-like receptor and human leukocyte antigen genotypes on the efficacy of immunotherapy in acute myeloid leukemia

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.

Killer‐cell immunoglobulin‐like receptors on the cusp of modern immunogenetics

“…Elin Bernson has assessed the impacts of KIR/HLA genotypes in non-transplanted acute myeloid leukaemia. 13 The data showed that patients carrying the KIR B haplotype and/or with a 'missing ligand' genotype tended to have high natural cytotoxicity receptor expression and improved clinical outcome. In the session on infection, chaired by Becca Asquith, she presented mathematical modelling of host-virus dynamics and data from in vitro T-cell survival assays that support the hypothesis that inhibitory KIR, in the presence of their HLA class I ligands, enhance CD8 + T-cell control of three viral infectionshepatitis C virus, HIV and human T-lymphotrophic virus.…”

“…The data support the previously reported association of the Cen‐B haplotype motif with reduced relapse. Elin Bernson has assessed the impacts of KIR/HLA genotypes in non‐transplanted acute myeloid leukaemia . The data showed that patients carrying the KIR B haplotype and/or with a ‘missing ligand’ genotype tended to have high natural cytotoxicity receptor expression and improved clinical outcome.…”

Cytomegalovirus Serostatus Affects Autoreactive NK Cells and Outcomes of IL2-Based Immunotherapy in Acute Myeloid Leukemia

“…KIR and KIR ligands were analyzed using the One Lambda KIR SSO Genotyping Test and the Olerup SSP KIR HLA Ligand kit, respectively, as described elsewhere (33). Patients were dichotomized based on concordance/discordance between their KIR and HLA genotypes.…”

“…Studies suggest that highly differentiated CMV-induced NK cells are important antileukemic effector cells in AML patients undergoing allo-SCT (4, 16,39). However, other studies propose that NS-iKIR NK cells might exert antineoplastic effector functions after immunomodulatory therapy (26,30,32,33). The high proportion of highly mature, adaptive NK cells along with the low proportion of NS-iKIR NK cells in CMV þ patients led us to examine the impact of CMV serostatus on clinical outcome.…”

“…Under resting conditions, these potentially autoreactive, "unlicensed" NK cells have limited cytotoxic capacity (28,29). However, immune perturbations, especially in the context of cancer, may activate these NK cells to become effector cells, as they do not express inhibitory receptors that can be targeted by malignant cells (26,(30)(31)(32)(33).…”