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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 CD56 bright 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.

[This corrects the article DOI: 10.3389/fimmu.2021.796072.].

BackgroundThe natural killer (NK) complex (NKC) harbors multiple genes such as KLRC1 (encoding NKG2A) and KLRK1 (encoding NKG2D) that are central to regulation of NK cell function. We aimed at determining to what extent NKC haplotypes impact on NK cell repertoire and function, and whether such gene variants impact on outcome of IL-2-based immunotherapy in acute myeloid leukemia (AML).MethodsGenotype status of NKG2D rs1049174 and NKG2A rs1983526 was determined using the TaqMan-Allelic discrimination approach. To dissect the impact of single nucloetide polymorphim (SNP) on NK cell function, we engineered the K562 cell line with CRISPR to be killed in a highly NKG2D-dependent fashion. NK cells were assayed for degranulation, intracellular cytokine production and cytotoxicity using flow cytometry.ResultsIn AML patients receiving immunotherapy, the NKG2A gene variant, rs1983526, was associated with superior leukemia-free survival and overall survival. We observed that superior NK degranulation from individuals with the high-cytotoxicity NKG2D variant was explained by presence of a larger, highly responsive NKG2A+ subset. Notably, NK cells from donors homozygous for a favorable allele encoding NKG2A mounted stronger cytokine responses when challenged with leukemic cells, and NK cells from AML patients with this genotype displayed higher accumulation of granzyme B during histamine dihydrochloride/IL-2 immunotherapy. Additionally, among AML patients, the NKG2A SNP defined a subset of patients with HLA-B-21 TT with a strikingly favorable outcome.ConclusionsThe study results imply that a dimorphism in the NKG2A gene is associated with enhanced NK cell effector function and improved outcome of IL-2-based immunotherapy in AML.

HLA-B alleles are associated with outcomes in various pathologies, including autoimmune diseases and malignancies. The encoded HLA-B proteins are pivotal in antigen presentation to cytotoxic T cells, and some variants containing a Bw4 motif also serve as ligands to the killer immunoglobulin-like receptors (KIR) 3DL1/S1 of NK cells. We investigated the potential impact of HLA-B genotypes on the efficacy of immunotherapy for relapse prevention in acute myeloid leukemia (AML). Seventy-eight non-transplanted AML patients receiving HDC/IL-2 in the post-consolidation phase were genotyped for HLA-B and KIR genes. HLA-B*44 heralded impaired LFS (leukemia-free survival) and overall survival (OS), but the negative association with outcome was not shared across alleles of the HLA-B44 supertype. Notably, HLA-B*44 is one of few HLA-B44 supertype alleles containing a Bw4 motif with a threonine at position 80, which typically results in weak binding to the inhibitory NK receptor, KIR3DL1. Accordingly, a strong interaction between KIR3DL1 and Bw4 was associated with superior LFS and OS (p = 0.014 and p = 0.027, respectively). KIR3DL1+ NK cells from 80 T-Bw4 donors showed significantly lower degranulation responses and cytokine responses than NK cells from 80I-Bw4 donors, suggesting impaired KIR3DL1-mediated education in 80 T-Bw4 subjects. We propose that presence of a strong KIR3DL1+–Bw4 interaction improves NK cell education and thus is advantageous in AML patients receiving HDC/IL-2 immunotherapy for relapse prevention.

The challenge of solid waste management has become a major global concern, drawing extensive research interest internationally. In particular, waste glass has gained attention for its growing use in mortar and concrete production as a sustainable alternative, serving as a partial replacement for coarse aggregate, fine aggregate, and cement. However, research on the utilization of waste glass powder in cement paste and its effects on the fresh, mechanical, durability, and microstructural properties has been relatively limited. This article seeks to address this issue by focusing on the incorporation of waste glass powder as a partial replacement for cement across eight different ratios, ranging from 0 to 50%. The study explores the impacts of these ratios on paste flow, compressive strength, and flexural strength, as well as the microstructural properties of the cement paste. Furthermore, it examines how the inclusion of glass affects the reduction of paste strength when subjected to acidic conditions. The findings revealed that as the amount of waste glass powder in the cement mixture increase, its workability improved. Moreover, compressive strength increased with higher percentages of waste glass powder, peaking at 20%, after which it declined. However, the ideal dosage for achieving maximum flexural strength was identified as 15% waste glass powder. Additionally, incorporating waste glass powder into the cement paste mixtures significantly enhanced their resistance to acids, as evidenced by a 10% increase in residual compressive strength and a reduced weight loss compared to the control mixture. Finally, according to microstructural analyses, specifically XRD and SEM examinations, the inclusion of waste glass powder results in the generation of a greater amount of C-S-H gels during pozzolanic reactions. As a result, this enhances both the mechanical strength and durability of the cement paste.

Contemporary construction practices increasingly recognize the utilization of waste materials as a methodological imperative for mitigating waste accumulation and advancing environmental remediation. This article explores the incorporation of waste glass granules as a partial substitute for coarse aggregates in conventional concrete, maintaining an equivalent coarse aggregate size range (9.5–12.5 mm) while varying the replacement ratios, specifically 5%, 10%, 20%, 30%, and 50%. The study investigates the impact of this substitution on key concrete properties, including compressive strength, flexural strength, density, water absorption, and permeability. The findings reveal that the utilization of waste glass granules, possessing a higher density compared to the original coarse aggregate, leads to an increase in the overall concrete density. Furthermore, the incorporation of glass granules enhances concrete impermeability and reduces water absorption. However, it is observed that the introduction of waste glass granules has an adverse effect on both compressive and flexural strengths of the concrete, with the magnitude of this effect escalating with higher replacement rates. The study identifies that the optimal replacement rate for waste glass granules, with minimal impact on concrete strength, stands at 15%.