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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: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE214042 | GEO | 2022/09/26

REPOSITORIES: GEO

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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: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.

2022-09-20 | E-MTAB-12228 | 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

Methylation in Adaptive Natural Killer cells after exposure to NKG2C agonist antibodies for 7 days

Project description:Natural Killer cells from cytomegalovirus positive individuals (i.e. adaptive NK) where cultured for seven days with either control antibody, an NKG2C agonist antibody, or an antibody agonist to NKG2C and NKG2A

2019-06-30 | GSE131973 | GEO

Gene expression profiling of NKG2C+ NK cells generated from inflammatory CD34+DNAM-1brCXCR4+ and Lin-CD34- CD16+CD56- blood precursors

Project description:There is limited knowledge on the origin and development of the ample spectrum of human NK cells, particularly of specialized NK subsets. Here, we characterized the NK cell progeny of CD34+DNAM-1bright CXCR4+ precursors that reside in healthy bone marrow and circulate in the peripheral blood (PB) of patients with chronic infections/inflammation. including HIV, HCV or HCMV reactivation after HSC transplantation. Unlike conventional CD34+ precursors they rapidly differentiated in vitro into cytotoxic, IFNγ-secreting CD94/NKG2C+KIR+CD57+ maturing NK cell progenies with HCMV-inhibiting activity. Progeny characterization led also to identification of an additional new PB Lin-CD56-CD16+ precursor giving rise to the same CD94/NKG2C+KIR+CD57+ maturing NK cell progenies. Microarray analysis of NK cell progenies revealed a signature compatible with maturing adaptive NK cells. In vivo circulation of multiple common lymphocyte precursors with rapid development to NKG2C+ NK cell progeny is steadily occurring and may thus be a crucial resource for the prompt control of HCMV. We used microarray to compare the transcriptional profiles of human NKG2C+ NK cells derived from i) CD34+DNAM1brightCXCR4+ precursors, ii) Lin-CD34-CD16+CD56- precursors, iii) peripheral blood.

2020-12-31 | GSE136570 | GEO

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

A discrete subset of epigenetically primed human NK cells mediates antigen-specific immune responses

Project description:Adaptive features of natural killer (NK) cells have been reported in various species with different underlying mechanisms. It is unclear, however, which NK cell populations are capable of mounting antigen-specific recall responses, and how such functions are regulated at the molecular level. Here we identify and characterize a discrete population of CD49a+CD16- NK cells in the human liver that display increased epigenetic potential to elicit memory responses and has the functional properties to exert antigen-specific immunity on the skin as an effector site. Integrated chromatin-based epigenetic and transcriptomic profiling revealed unique characteristics of hepatic CD49a+CD16- NK cells when compared to conventional CD49a-CD16+ NK cells thereby defining active genomic regions and molecules underpinning distinct NK cell reactivity. In contrast to conventional NK cells, our results suggest adaptive CD49a+CD16- NK cells to be able to bypass the KIR receptor-ligand system upon antigen-specific stimulation. Furthermore, these cells were highly migratory towards chemokine gradients expressed in epicutaneous patch test lesions as an effector site of adaptive immune responses of the skin. These results define pathways operative in human antigen-specific memory NK cells and provide a roadmap for harnessing this NK cell subset for specific therapeutic or prophylactic vaccine strategies.

2020-10-15 | GSE158485 | 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

IFNγ mediates the resistance of tumor cells to distinct NK cell subsets.

Project description:Tumor resistance to immune cells remains a major obstacle for successful treatment. NK cells are emerging tools for cancer therapy. However, due to differential and subset-specific expression of inhibitory NK cell receptors, often only subsets of NK cells exert reactivity against particular cancer types. Using a genome-wide CRISPR/Cas9 knockout (KO) screen in melanoma, we revealed resistance factors against NK cell attack and evaluated their differential impact on NK cell subpopulations. We show that melanoma cells deficient in antigen-presenting machinery or the IFNγ signaling pathway displayed enhanced sensitivity to NK cell killing. Treatment with IFNγ induced melanoma cell resistance that depended on B2M required for both classical and non-classical MHC-I expression. HLA-E mediated melanoma cell resistance to NKG2A+ KIR-, and partially to NKG2A+ KIR+ NK cells. Treatment of NK cells with the NKG2A blocking monalizumab resulted in enhanced NK cell reactivity to similar extent as deletion of HLA-E in melanoma cells. The combination of monalizumab with lirilumab, blocking KIR2 receptors, together with DX9, an anti-KIR3DL1 mAb, was required to restore the response of all NK cells against IFNγ-pretreated tumor cells of different origins. Our data reveal insights into NK cell subset reactivity and strategies how to leverage their full anti-tumor potential.

2024-07-10 | GSE261626 | GEO

Tumor-induced Natural Killer cell dysfunction is a rapid and reversible process uncoupled from the expression of immune checkpoints

Project description:Natural Killer (NK) cells often become dysfunctional during tumor progression but the molecular mechanisms underlying this phenotype remain unclear. To explore this phenomenon, we set up new mouse lymphoma models activating or not NK cells. Both tumor types elicited IFN-I production, leading to the expression of a T cell exhaustion-like signature in NK cells, which included immune checkpoint proteins (ICPs). However, NK cell dysfunction occurred exclusively in the tumor model that triggered NK cell activation. Additionally, ICP positive NK cells demonstrated heightened reactivity compared to negative ones. Furthermore, the onset of NK cell dysfunction was swift and temporally dissociated from the induction of ICPs, which occurred as a later event during tumor growth. Finally, NK cell responsiveness was restored when stimulation was discontinued, and IL-15 had a positive impact on this reversion. Therefore, our data demonstrate that the reactivity of NK cells is dynamically controlled, and that NK cell dysfunction is a reversible process uncoupled from the expression of ICPs

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