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Genome-wide CRISPR screen reveals cancer cell resistance to NK cells induced by NK-derived IFN-gamma

ABSTRACT: The anti-leukemia activity of NK cells helps to prevent relapse during hematopoietic stem cell transplantation in leukemia patients. However, the factors that determine sensitivity or resistance of leukemia cells in the context of NK-mediated cytotoxicity are not well established. Here we performed a genome-wide CRIPSR screen in the human chronic-myelogenous-leukemia (CML) cell line K562 to identify genes that regulate vulnerability of leukemia cells to killing by primary human NK cells. Distribution of guide RNAs (gRNAs) in K562 cells that survived co-incubation with NK cells showed that loss of NCR3LG1, which encodes the ligand of the natural cytotoxicity receptor NKp30, protected K562 cells from killing. In contrast, loss of genes that regulate pathways for antigen-presentation and interferon-gamma-signaling increased the vulnerability of K562 cells. Addition of IFN-gamma neutralizing antibody increased the susceptibility of K562 cells to NK-mediated killing. Upregulation of MHC class I on K562 cells after co-incubation with NK cells was dependent on IFNGR2. Analysis of RNA-seq data from The Cancer Genome Atlas (TCGA) showed that low IFNGR2 expression in cancer tissues associated with improved overall survival in acute myeloid leukemia (AML) and Kidney Renal Clear Cell Carcinoma (KIRC) patients. Our results showing that upregulation of MHC class I by NK-derived IFN-gamma leads to resistance to NK cytotoxicity suggest that targeting IFN-gamma responses might be a promising approach to enhance NK cell anti-cancer efficacy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139313 | GEO | 2019/10/24

REPOSITORIES: GEO

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MicroRNA-1 regulates goat uterine NK cells function by targeting tumor necrosis factor-like weak inducer of apoptosis (TWEAK)

Project description:MicroRNAs (miRNAs) play important roles in regulating immune response of natural killer (NK) cells, a critical effectors against malignancy and infection. Here, miRNAs profiles of goat uterine NK (uNK) cells and peripheral blood NK (pNK) cells were examined, and a novel miRNAs, miR-1, that is lowly expressed in uNK cells compared to pNK cells were identified. We further demonstrated that miR-1 directly target TWEAK gene in NK cells, a negative regulator of NK cell cytotoxicity. Moreover, our data revealed that an increased miR-1 expression was observed in uNK cells incubated with somatic cell nuclear transfer (SCNT) conditioned medium compared to those incubated with in vitro fertilization (IVF) conditioned medium, and an inverse correlation was detected between miR-1 expression and TWEAK mRNA and protein expression in both groups. Interestingly, miR-1 mediated suppression of TWEAK in uNK cells in response to SCNT conditioned medium incubation was accompanied with an increased cytotoxicity and IFN-γ expression compared to control group. Furthermore, miR-1 inhibitor transfection abrogate the enhanced cytotoxicity of uNK cells incubated with SCNT conditioned medium, which was accompanied with an increased TWEAK expression. Taken together, our results demonstrated that TWEAK regulated by miR-1 may play a key role in regulating goat uNK cells cytotoxicity and IFN-γ expression levels. In particularly, miR-1 mediated suppression of TWEAK may involved in the increased cytotoxicity of uNK cells in response to SCNT embryo incubation. These results provide a resource for studying the roles of miRNAs in goat NK cell biology and contribute to a better understanding of the physiologic significance of miRNAs in the regulation of NK cell function.

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Project description:The release of soluble ligands of activating Natural Killer (NK) cell receptors may represent a regulatory mechanism of NK cell function both in physiologic and in pathologic conditions. Here, we identified the extracellular matrix protein Nidogen-1 (NID1) as a ligand of NKp44, an important activating receptor expressed by activated NK cells. When released as soluble molecule, NID1 can regulate NK cell function by modulating NKp44-induced IFN-γ production or cytotoxicity. We also show that NID1 may be present at the cell surface. In this form or when bound to a solid support (bNID1), NID1 failed to induce NK cell cytotoxicity or cytokine release. However, analysis by mass spectrometry revealed that exposure to bNID1 can induce relevant changes in the proteomic profiles suggesting an effect on different, biological processes of human NK cells.

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NKp46 regulates type 1 innate lymphoid cell proliferation and function and anti-acute myeloid leukemia activity

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Histone methyltransferase Ezh2 negatively regulates NK cell terminal maturation and function

Project description:Deletion of Ezh2 promotes NK cell terminal differentiation and cytotoxicity with increased IFN-γ production by a potential target Pbx1.

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SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-g and NK cells [BALF_BloodNK_SARSWu_NHP]

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SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-g and NK cells [BALF_Macro_SARS_NHP]

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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

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

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