Corrigendum: Impact of NK Cell Activating Receptor Gene Variants on Receptor Expression and Outcome of Immunotherapy in Acute Myeloid Leukemia.
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ABSTRACT:
SUBMITTER: Hussein BA
PROVIDER: S-EPMC8793824 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
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Project description:Acute myeloid leukemia (AML) is a deadly disease and the most common leukemia in adult with clonal heterogeneity and abnormity in myeloid lineages, which has been recognized with high morbidity and mortality attributes to the recurrence and resistance to chemotherapy. Numerous literatures have indicated the encouraging progress in allogeneic hematopoietic stem cell transplantation (allo-HSCT) and chimeric antigen receptor-transduced T (CAR-T) cells. However, the outcomes of recurrent and refractory AML (r/rAML) patients with current strategies are still unsatisfactory, which largely due to the matching restriction as well as adverse reactions, including graft-versus-host disease (GvHD), neurotoxicity and cytokine release syndrome (CRS). State-of-the-art literatures have indicated CAR-transduced NK (CAR-NK) cells for the management of diverse hematologic malignancies including AML, which are recognized as novel weapons for reinforcing the specificity and cytotoxicity of autogenous and allogeneic "off-the-shelf" NK cells dispense with prior sensitization. Therefore, in this review, we mainly focus on the latest updates of alternative cell sources, therapeutic targets, CAR-modification and delivery strategies, standardization and productization, together with prospective and challenges of CAR-NK cell-based cytotherapy, which will collectively benefit the further development of novel treatment paradigms for combating AML via both CAR-dependent and NK cell receptor-dependent signaling cascades in future.
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Project description:Natural killer (NK) cell function is regulated by inhibitory receptors, such as the family of killer immunoglobulin-like receptors (KIRs) and the NKG2A/CD94 heterodimer. These receptors recognize cognate HLA class I molecules on potential target cells, and recent studies imply that an HLA-B dimorphism at position -21 in the gene segment encoding the leader peptide dictates whether NK cell regulation primarily relies on the KIRs or the NKG2A/CD94 receptor. The impact of this HLA-B dimorphism on NK cell-mediated destruction of leukemic cells or on the course of leukemia is largely unknown. In a first part of this study, we compared functions of NK cells in subjects carrying HLA-B -21M or 21T using interleukin-2 (IL-2)-activated NK cells and leukemic cells from patients with acute myeloid leukemia (AML). Subjects carrying HLA-B -21M harbored better-educated NKG2A+ NK cells and displayed superior capacity to degranulate lytic granules against KIR ligand-matched primary leukemic blasts. Second, we aimed to define the potential impact of HLA-B -21 variation on the course of AML in a phase 4 trial in which patients received IL-2-based immunotherapy. In keeping with the hypothesis that 21M may be associated with improved NK cell functionality, we observed superior leukemia-free survival and overall survival in -21M patients than in -21T patients during IL-2-based immunotherapy. We propose that genetic variation at HLA-B -21 may determine the antileukemic efficacy of activated NK cells and the clinical benefit of NK cell-activating immunotherapy.
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