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Adaptive single-KIR+NKG2C+ NK cells expanded from superdonors show potent missing-self reactivity and efficiently control HLA-mismatched acute myeloid leukemia

ABSTRACT: Describe a novel GMP-compliant protocol to expand clinically relevant numbers of adaptive NK cells from third-party ‘superdonors’. These NK cells provide strong reactivity in a mouse model of AML as well as against primary AML blasts ex vivo. How this study might affect research, practice or policy: These pre-clinical data demonstrate the feasibility of an NK cell-based cell therapy with a non-engineered and yet highly specific NK cell population, representing the first route to clinical testing of missing-self recognition.

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Homo sapiens

SUBMITTER: Karl-Johan Malmberg

PROVIDER: E-MTAB-12228 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Adaptive single-KIR+NKG2C+ NK cells expanded from superdonors show potent missing-self reactivity and efficiently control HLA-mismatched acute myeloid leukemia

Project description:Adoptive natural killer (NK) cell therapy in combination with hematopoietic stem cell transplantation (HSCT) can provide cure for acute myeloid leukemia (AML) but is in part dependent on variable NK cell reactivity. Adaptive NK cells are a highly potent NK cell subsets that can be utilized to maximize ‘missing-self’ reactivity against tumor cells. What this study adds: It describes a novel GMP-compliant protocol to expand clinically relevant numbers of adaptive NK cells from third-party ‘superdonors’. These NK cells provide strong reactivity in a mouse model of AML as well as against primary AML blasts ex vivo. How this study might affect research, practice or policy: These pre-clinical data demonstrate the feasibility of an NK cell-based cell therapy with a non-engineered and yet highly specific NK cell population, representing the first route to clinical testing of missing-self recognition.

2022-09-26 | GSE214042 | GEO

Transcriptome dynamics during interaction of NK cells and Candida albicans

Project description:NK cells are part of the innate immune system and therefore directly involved in the response to a Candida albicans infection. Our aim is to better understand the interaction of NK cells and C.albicans cells. Natural Killer cells (NK cells) were isolated from blood of 3 different donors and coincubated with Candida albicans. Transcriptome analysis was performed after 3 and 6 hours using an Illumina HumanHT-12 v4 Expression BeadChip.

2016-06-01 | E-MTAB-4105 | biostudies-arrayexpress

Whole Genome sequencing of a normal karyotype AML cell line

Project description:Normal Karyotype acute myeloid leukemia (NK-AML) represents approximately 50% of all cases of AML which patients develop. Most AML cell lines are highly abnormal and therefore not good models for investigating NK-AML biology a novel AML cell line, CG-SH, was recently estabished and here we characterize the gene expression and mutations present through high-throughput sequencing of RNA and genomic DNA using a HiSeq 2000 The overall design of the experiment was to characterize, at single base pair resolution, all of the genetic defects present in a novel normal karyotype cell line, CG-SH

2013-12-31 | E-GEOD-40199 | biostudies-arrayexpress

RNA-Seq of FACS-sorted, KIR-CD39-,KIR+CD39- and KIR+CD39+, Uterine NK cells (uNK cells) from human decidual samples

Project description:Uterine NK cells (uNK cells) form a distinct immune cell population in the endometrium and decidua. Here, we FACS-sorted KIR-CD39-,KIR+CD39- and KIR+CD39+ uNK cells from decidual samples.

2021-02-19 | E-MTAB-8709 | biostudies-arrayexpress

Total RNA sequencing of KIR+ and KIR- NK cells from patients experiencing or not a Cytomegalovirus reactivation after haploidentical hematopoietic stem cell transplantation

Project description:AIM: To investigate the adaptive properties of NK cells, by comparing the expression profiles of FACS-sorted KIR+ (CD158b1b2j) and KIR- NK cells from patients experiencing or not a Cytomegalovirus (HCMV) reactivation after haploidentical hematopoietic stem cell transplantation (h-HSCT). RESULTS: Our flow cytometry data demonstrate that KIR+ NK cells are expanded in h-HSCT patients upon HCMV reactivation, thus suggesting that these cells could be important in controlling the viral infection and could be endowed with adaptive features. By comparing the expression profiles of KIR+ and KIR- NK cells from reacivated patients, we demonstrated a cytokine receptor unbalance, a prevalence of pathways associated to mitochondrial respiration and consequent ATP synthesis, a downregulation of genes involved in epigenetic reprogramming, all properties attributable adaptive NK cells. By comparing the molecular fingerprint of KIR+ NK cells between patients experiencing a HCMV reactivation and not reactivated patients, we observed in reactivated group an upregulation of INFG expression and in genes involved in Signaling receptor activity and MHC class II antigen presentation , thus strengthens the hypothesis that our KIR+ NK cells in reactevated h-HSCT patients are able to produce IFN-γ driving specific responses upon re-stimulation. However, the enrichment in PD-1 signaling, let us speculate that KIR+ NK cells from reactivated h-HSCT patients have impaired effector-functions.

2020-10-29 | GSE160362 | GEO

Defective NK cells in AML patients at diagnosis are associated with blast transcriptional signatures of immune evasion

Project description:Acute myeloid leukemia (AML) is a heterogeneous group of malignancies which may be sensitive to the natural killer (NK) cell anti-tumor response. However, NK cells are frequently defective in AML. Here, we found in an exploratory cohort (n = 46) that NK-cell status at diagnosis of AML separated patients in two groups with a different clinical outcome. Patients with a deficient NK-cell profile, including reduced expression of some activating NK receptors (e.g. DNAM-1, NKp46 and NKG2D) and decreased IFN-g production, had a significantly higher risk of relapse (P = 0.03) independently of cytogenetic classification in multivariate analysis. Patients with defective NK cells showed a profound gene expression decrease in AML blasts for cytokine and chemokine signaling (e.g. IL15, IFNGR1, IFNGR2, CXCR4), antigen processing (e.g. HLA-DRA, HLA-DRB1, CD74) and adhesion molecule pathways (e.g. PVR, ICAM1). A set of 388 leukemic classifier genes defined in the exploratory cohort was independently validated in a multicentric cohort of 194 AML patients. In total, these data evidenced the interplay between NK-cells and AML blasts at diagnosis allowing an immune-based stratification of AML patients independently of clinical classifications. 5 normal AML cells were compared with 8 NK deficient AML cells.

2015-07-24 | E-GEOD-50928 | biostudies-arrayexpress

Defective NK cells in AML patients at diagnosis are associated with blast transcriptional signatures of immune evasion

Project description:Acute myeloid leukemia (AML) is a heterogeneous group of malignancies which may be sensitive to the natural killer (NK) cell anti-tumor response. However, NK cells are frequently defective in AML. Here, we found in an exploratory cohort (n = 46) that NK-cell status at diagnosis of AML separated patients in two groups with a different clinical outcome. Patients with a deficient NK-cell profile, including reduced expression of some activating NK receptors (e.g. DNAM-1, NKp46 and NKG2D) and decreased IFN-g production, had a significantly higher risk of relapse (P = 0.03) independently of cytogenetic classification in multivariate analysis. Patients with defective NK cells showed a profound gene expression decrease in AML blasts for cytokine and chemokine signaling (e.g. IL15, IFNGR1, IFNGR2, CXCR4), antigen processing (e.g. HLA-DRA, HLA-DRB1, CD74) and adhesion molecule pathways (e.g. PVR, ICAM1). A set of 388 leukemic classifier genes defined in the exploratory cohort was independently validated in a multicentric cohort of 194 AML patients. In total, these data evidenced the interplay between NK-cells and AML blasts at diagnosis allowing an immune-based stratification of AML patients independently of clinical classifications. Gene expression analysis were performed on CD56bright and CD56dim NK cells sorted from patients with impaired or normal CD56bright NK cells (n=2 for each patients? group) and from 3 HC

2015-07-24 | E-GEOD-34885 | biostudies-arrayexpress

RNA-Seq of human regulatory T cells and effector T cells cultured at standard 37C temperature and in mild hypothermia (33C).

Project description:Regulatory T cells (Tregs) play crucial role in maintenance of peripheral tolerance. Numerous clinical trials confirmed safety and efficacy of Treg treatment of for deleterious immune responses. However, Tregs lose their characteristic phenotype and suppressive potential during expansion ex vivo. In our experiment we demonstrate that mild hypothermia of 33C induces robust proliferation of human Tregs, preserves expression of FoxP3, CD25 and Helios, and prevents TSDR methylation during culture in vitro. Tregs expanded at 33C showed stronger immunosuppressive potential and anti-inflammatory phenotype. We show that a simple change in temperature can preserve Treg stability, function and accelerate their proliferation in vitro.

2017-10-04 | E-MTAB-5322 | biostudies-arrayexpress

FLT3 gene-expression signature in normal karyotype AML

Project description:Acute myeloid leukemia with normal karyotype (NK-AML) represents a cytogenetic grouping with intermediate prognosis but substantial molecular and clinical heterogeneity. Within this subgroup, presence of FLT3 (FMS-like tyrosine kinase 3) internal tandem duplication (ITD) mutation predicts less favorable outcome. The goal of our study was to discover gene-expression patterns correlated with FLT3-ITD mutation, and to evaluate the utility of a FLT3 signature for prognostication. The dataset comprises gene-expression profiles of 137 normal karyotype acute myeloid leukemia (NK-AML) specimens carried out using Stanford cDNA microarrays, to accompany the study of L Bullinger et al. For each array, Channel 2 represents Cy5-labeled NK-AML RNA, and Channel 1 Cy3-labeled universal reference RNA. Keywords: Logical Set DNA microarrays were used to profile gene expression in a training set of 65 NK-AML cases. Supervised analysis was applied to build a gene expression-based predictor of FLT3-ITD mutation status. The predictor was then evaluated by classifying expression profiles from an independent test set of 72 NK-AML cases.

2008-02-27 | E-GEOD-8043 | biostudies-arrayexpress

Gene expression profiling in AML with normal karyotype: A multicenter study investigating molecular markers in 251 cases

Project description:Acute myeloid leukemia (AML) is a heterogeneous disease and AML with normal karyotype (AML-NK) is categorized as an intermediate-risk group. Over the past years molecular analyses successfully identified biomarkers that will further allow to dissecting clinically meaningful subgroups in this disease. Thus far, somatic mutations were identified which elucidate the disturbance of cellular growth, proliferation, and differentiation processes in hematopoietic progenitor cells. In AML-NK, acquired gene mutations with prognostic relevance were identified for FLT3, CEBPA, and NPM1. FLT3-ITD mutations were associated with short relapse-free and overall survival, while mutations in CEBPA or NPM1 (without concomitant FLT3-ITD) had a more favorable outcome. Here, we present a multicenter study investigating gene expression profiles of 251 cases of de novo AML-NK. In three centers whole-genome microarray analyses were performed to delineate robust and common expression signatures for molecular markers in AML-NK. All samples were obtained from untreated patients at the time of diagnosis. Cells used for microarray analysis were collected from the purified fraction of mononuclear cells after Ficoll density centrifugation (Dresden, n=78; Munich, n=97; Ulm, n=77). Each laboratory performed its routine diagnostic algorithms, including the characterization of molecular markers.

2009-12-31 | E-GEOD-15434 | biostudies-arrayexpress

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