Abstract
Natural killer cells are important effector cells in the immune response against myeloid malignancies. Previous studies show that the expression of activating NK cell receptors is pivotal for efficient recognition of blasts from patients with acute myeloid leukemia (AML) and that high expression levels impact favorably on patient survival. This study investigated the potential impact of activating receptor gene variants on NK cell receptor expression and survival in a cohort of AML patients receiving relapse-preventive immunotherapy with histamine dihydrochloride and low-dose IL-2 (HDC/IL-2). Patients harboring the G allele of rs1049174 in the KLRK1 gene encoding NKG2D showed high expression of NKG2D by CD56bright NK cells and a favorable clinical outcome in terms of overall survival. For DNAM-1, high therapy-induced receptor expression entailed improved survival, while patients with high DNAM-1 expression before immunotherapy associated with unfavorable clinical outcome. The previously reported SNPs in NCR3 encoding NKp30, which purportedly influence mRNA splicing into isoforms with discrete functions, did not affect outcome in this study. Our results imply that variations in genes encoding activating NK cell receptors determine receptor expression and clinical outcome in AML immunotherapy.
Highlights
Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by uncontrolled expansion of myeloid progenitors at the expense of normal hematopoiesis
We have reported that acute myeloid leukemia (AML) patients strongly upregulate expression of NKp30 in response to histamine dihydrochloride (HDC)/IL-2 immunotherapy [16], and that high NKp30 expression is associated with improved leukemia-free survival (LFS) and overall survival (OS) in elderly AML patients [35]
We investigated how gene variants of the activating natural killer (NK) cell receptors including NKG2D, DNAM-1 and NKp30 impact on clinical outcome and receptor expression in a cohort of AML patients receiving IL-2-based immunotherapy
Summary
Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by uncontrolled expansion of myeloid progenitors at the expense of normal hematopoiesis. The NKp30C isoform was reported to negatively impact the prognosis of patients with melanoma and metastatic gastrointestinal stromal tumors (GIST) [29, 30] These previous studies incited us to investigate to what extent genetic variation at SNPs that encode activating NK cell receptors, including NKG2D, DNAM-1 and NKp30, affect expression levels and outcome in AML patients receiving NK cell-activating immunotherapy. PBMCs from before and after first treatment cycle were thawed and analyzed by flow cytometry to assess expression of NK activating receptors including NKG2D, DNAM-1 and NKp30 (expression presented in median fluorescence intensity; MFI). Four NK cell activating receptor gene variants including NKp30 (rs986475), NKp30 (rs1052248), DNAM-1 (rs763361) and NKG2D (rs1049174) were genotyped using the TaqMan-Allelic discrimination with Applied Biosystem 7500 Fast Real-Time PCR System. Impact of age on survival was further analyzed using multivariate cox regression analysis
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