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Diversity of molecular interactions between NK cells and acute leukemic cells: KIR2DL5 drastically limits NK cell responses against leukemic cells

ABSTRACT: Diversity of molecular interactions between NK cells and acute leukemic cells: KIR2DL5 drastically limits NK cell responses against leukemic cells

PROVIDER: PRJNA1183760 | ENA |

REPOSITORIES: ENA

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Diversity of molecular interactions between NK cells and acute leukemic cells: KIR2DL5 drastically limits NK cell responses against leukemic cells

Project description:NK cells naturally recognize and eliminate leukemic cells. However, the molecular interactions that govern these responses are diverse due to the large number of activating and inhibitory NK receptors that modulate NK functions and the diversity of corresponding ligands that are differentially expressed in acute lymphoblastic and myeloid leukemias. We identified resting NKG2A+ NK cells and NKG2A+KIR+ NK cell subsets that are most effective in eliminating lymphoid and myeloid leukemic cells respectively. The NKG2A+KIR+/-CD57- subsets show high expression of activating receptors and a functional transcriptomic profile, but differ in KIR2DL5 expression. The frequency of KIR2DL5+ NK cells increases with the number of expressed KIR. Furthermore, KIR2DL5 is preferentially co-expressed with KIR2DL1 and is negatively regulated by NKG2A. Of note, CD57 expression, regardless of the subset considered, is associated with reduced receptor expression, consistent with its reduced cytotoxic potential. Furthermore, we have shown that molecular interactions between NK cells and leukemic cells influence NK cell responses, particularly the inhibitory KIR2DL5-PVR axis. The integration of these data is of importance for the optimization of NK cell-based immunotherapies, as the selection of NK cell donors represents a key parameter for the improvement of these therapies.

2025-07-14 | GSE281383 | GEO

Simulated Microgravity Impairs Human NK Cell Cytotoxic Activity Against Space Radiation-Relevant Leukemic Cells

Project description:Natural killer (NK) cells are important effectors of the innate immune system. Unlike T cells, NK cells do not require antigen-priming, making them an important first-line of defense against malignant cells. Because of the potential for increased cancer risk as a result of astronaut exposure to space radiation, we performed studies to determine whether conditions of microgravity present during spaceflight affects the body’s natural defenses against leukemogenesis. Human NK cells were cultured for 48 hours under normal gravity and simulated microgravity (smG), and cytotoxicity against K-562 (CML) and MOLT-4 (T-ALL) cell lines was measured using standard methodology or under continuous conditions of smG. Even this brief exposure to smG markedly reduced NK cytotoxicity against both leukemic cells using standard assay procedures, and these deleterious effects were even more pronounced in continuous smG. RNA-seq performed on NK cells from two healthy donors provided insight into the mechanism(s) by which smG reduced cytotoxicity. Given our prior report that human HSC exposed to simulated space radiation gave rise to T-ALL in vivo, the reduced cytotoxicity against MOLT-4 is striking and raises the possibility thatmG may add to astronaut risk of leukemogenesis during prolonged missions beyond LEO.

2024-08-22 | GSE255750 | GEO

Cytotoxic NK cells impede response to checkpoint immunotherapy in melanoma with an immune-excluded phenotype

Project description:The inability of lymphocytes to infiltrate the tumor nest drastically limits immune checkpoint blockade (ICB) responsiveness. Analyzing the immune landscape of matched pre- and early on-treatment biopsies of melanoma patients undergoing ICB therapy, we observed a significant increase in cytotoxic NK cells in early on-treatment biopsies from non-responders. Spatial OMICs revealed that while NK cells colocalized with CD8 T cells within the tumor bed in responding lesions, they were excluded from the tumor parenchyma in non-responding lesions. Strikingly, depletion of NK cells using a NK1.1 antibody or the FDA-approved drug Daratumumab in a unique melanoma mouse model exhibiting an immune-excluded phenotype unleashed immune infiltration of the tumor core and tumor clearance upon ICB exposure. Mechanistically, we show that NK cells are actively recruited to immune-excluded areas upon ICB exposure via the chemokine receptor CX3CR1 to suppress tumor infiltration and antitumor function of CD8 T cells, possibly by promoting ferroptosis.

2025-05-28 | GSE292854 | GEO

Characterization of BCR::ABL1-negative NK cells exposed to leukemic microenvironment in a mouse model of Chronic Myeloid Leukemia (https://doi.org/10.1182/bloodadvances.2024014592)

Project description:Natural killer (NK) cells play an integral role in immunosurveillance against myeloid malignancies, with their mature phenotype and abundance linked to prolonged treatment-free remission in chronic myeloid leukemia (CML). However, NK cell function is suppressed during the disease, and the orchestrators of this impairment are not fully understood. Using a chimeric BCR::ABL1+ CML mouse model, we characterized the impact of the leukemic microenvironment on NK cell function and gene transcription. To address the latter, we profiled NK cells from spleen and bone marrow of CML and healthy mice by single-cell RNA sequencing. We revealed an inflammatory cytokine response in CML-exposed NK cells, highlighted by the tumor necrosis factor-a (TNFa)-induced gene signature, upregulation of TNFa receptor TNFR2, and enrichment of SOCS family genes such as Cish, the critical NK cell checkpoint. Ex vivo exposure of healthy NK cells to leukemic soluble factors compromised target-specific NK cell degranulation, which was partially rescued by inhibiting Cish or TNFa - candidate targets reveiled by scRNA-seq. In alignment with these findings, NK cells from healthy donors displayed suppressed cytotoxicity when exposed to plasma from untreated CML patients, with a partial restoration upon Cish or TNFa inhibition. Furthermore, NK cells from newly diagnosed CML patients pre-destined for blast crisis showed an enrichment of the TNFa-induced pro-inflammatory gene signature identified in CML mice. These results suggest that targeting inflammatory signaling could enhance NK cell-based immunotherapies for CML.

2024-11-30 | GSE283212 | GEO

The transcription factor Rfx7 limits metabolism of NK cells promoting their maintenance and immunity

Project description:The transcription factor Rfx7 limits metabolism of NK cells promoting their maintenance and immunity

| PRJNA450613 | ENA

Simulated Microgravity Impairs Human NK Cell Cytotoxic Activity Against Space Radiation-Relevant Leukemic Cells

Project description:Simulated Microgravity Impairs Human NK Cell Cytotoxic Activity Against Space Radiation-Relevant Leukemic Cells

| PRJNA1076274 | ENA

Human Immune Gene Expression Profile in activated and expanded NK cells, TIGITKO NK cells, GD2.CAR NK cells and TIGITKOGD2.CAR NK cells

Project description:Human Immune Gene Expression Profile in activated and expanded NK cells, TIGITKO NK cells, GD2.CAR NK cells and TIGITKOGD2.CAR NK cells

| PRJNA1216524 | ENA

Comparative transcriptomics of porcine conventional blood NK cells, conventional liver NK cells and liver resident NK cells

Project description:Comparative transcriptomics of porcine conventional blood NK cells, conventional liver NK cells and liver resident NK cells

| PRJNA954776 | ENA

Protemics of Mettl3-deficient NK cells

Project description:With mass spectrometry， we aim to find the differentially expressed proteins in Mettl3-deficient NK cells

2021-07-20 | PXD025823 |

Cytokine-enhanced cytolytic activity of Exosomes from NK Cells

Project description:Natural killer (NK) cells are a type of innate lymphocytes that play key roles in immune surveillance against tumors and viral infection. NK cells distinguish abnormal cells from healthy cells by cell-cell interaction with cell surface proteins and then attack target cells via multiple mechanisms involving TRAIL, Fas Ligand, cytokine secretion, perforin, and granzymes. In addition, extracellular vesicles (EVs), including exosomes derived from NK cells (NK-EVs), possess cytotoxic capacity against tumor cells, but their characteristics and regulation by cytokines remain unknown. Here, we report that EVs derived from human NK-92 cells stimulated with IL-15 + IL-21 show enhanced cytotoxic capacity against tumor cells in a granzyme B independent manner. In addition, small RNA-seq and mass spectrometry analyses indicate that miRNA and protein profiles in EVs are altered by cytokine stimulation. We also show NK-EVs are taken up by target cells via macropinocytosis. Collectively, our findings reveal novel characteristics of NK-EVs and the mechanism of their incorporation into target cells.

2021-09-09 | PXD018982 | Pride

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