A Pan-Cancer Single Cell Panorama of Natural Killer Cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE212890 | GEO | 2023/08/22
REPOSITORIES: GEO
Similar Datasets
Project description:Pediatric patients with recurrent metastatic Ewing sarcoma (ES) have a dismal 5-year survival of < 30% largely secondary to treatment resistance in the tumor microenvironment (TME). Novel therapeutic approaches are desperately needed and represent an unmet need. Here, we developed a chimeric antigen receptor (CAR) expressing natural killer (NK) cell targeting melanoma cell adhesion molecule (MCAM) by electroporation of CAR mRNA into ex-vivo expanded NK cells. Expression of anti-MCAM CAR significantly and specifically enhanced NK cytotoxic activity compared to mock NK cells against MCAMhigh ES cells in vitro, and significantly reduced lung metastasis and extended animal survival in an orthotopic xenograft mouse model of ES. However, anti-MCAM CAR NK cells had minimal effects on decreasing primary tumor growth in vivo. We performed transcriptome profiling in patient-derived xenografts to identify the underlying mechanisms of NK cell resistance in ES TME.
2024-09-18 | GSE251936 | GEO
Project description:Natural Killer (NK) cells are important components of the immune system in the defense against tumor transformation. They release exosomes containing proteins and nucleic acids, including microRNAs (miRNAs) that play a role in the anti-tumor NK cell functions since they are able to recognize and kill cancer cells. In this study, we explored the miRNA content of NK exosomes by microarray as compared to their cellular counterpart and we identified a small subset of miRNAs highly expressed in NK exosomes.
2023-06-03 | GSE186056 | GEO
Project description:XPO1 is a nuclear export protein that is frequently overexpressed in cancer and functions as a driver of oncogenesis. Currently small molecules that target XPO1 are being used in the clinic as anti-cancer agents. We identify XPO1 as a target for natural killer (NK) cells. Using immunopeptidomics we have identified a peptide derived from XPO1 that can be recognized by the activating NK cell receptor KIR2DS2 in the context of HLA-C. The peptide can be endogenously processed and presented to activate NK cells specifically through this receptor. Although high XPO1 expression in cancer is commonly associated with a poor prognosis, we show that the outcome of specific cancers, such as hepatocellular carcinoma, can be substantially improved if there is concomitant evidence of NK cell infiltration. We thus identify XPO1 as a bona fide tumor antigen recognised by NK cells, that offers an opportunity for a personalized approach to NK cell therapy for solid tumors.
2024-10-17 | PXD053264 | Pride
Project description:Extranodal natural killer/T-cell lymphoma (NKTCL) is an aggressive Epstein-Barr virus (EBV)-associated lymphoma with heterogeneous tumor behaviors and clinical outcomes. Here, we profiled tumor microenvironment (TME) of NKTCL through single-cell transcriptome analysis of 137,304 cells from 10 tumor-blood pairs. We identified six malignant subtypes with diverse transcriptional signatures, among which LMP1+ NK_C9_CXCL13 was characterized with oncogenic and immunosuppressive potentials as well as an axial role in malignant transformation. Moreover, ligand-receptor analyses and multiplex immunofluorescent staining assays revealed intensive interactions among malignant NK, tumoral myeloid, and T cells, fostering immunosuppressive TME in NKTCL. Furthermore, co-culture assays revealed that malignant cells induced the development of immunosuppressive and pro-tumorigenic tumor-associated macrophages (TAMs) through high expression of CSF1 and hampered the recruitment of normal NK cells through broad secretion of a dipeptidylpeptidase DPP4 in NKTCL. Lastly, we revealed the inter-patient heterogeneity of NKTCL with distinct EBV transcription and TAM infiltration in multiple patient cohorts, of which high and low were favorable prognostic indicators for NKTCL patients, respectively. Collectively, for the first time to our knowledge, our study dissects the heterogeneous composition of NKTCL TME at single-cell resolution, which provides insights into understanding the pathogenic mechanisms of NKTCL and developing novel therapeutic strategies against NKTCL.
2024-01-03 | GSE203663 | GEO
Project description:Natural Killer cells (NK), a major constituent of innate immune system, have the ability to kill the transformed and infected cells without prior sensitization; can be put to immunotherapeutic use against various malignancies. NK cells discriminate between normal cells and transformed cells via a balance of inhibitory and activating signals induced by interactions between NK cell receptors and target cell ligands. Present study investigates whether expansion of NK cells could augment their anti-myeloma (MM) activity. For NK cell expansion, peripheral blood mononuclear cells from healthy donors and myeloma patients were co-cultured with irradiated K562 cells transfected with 4-1BBL and membrane-bound IL15 (K562-mb15-41BBL). A genome-wide profiling approach was performed to identify gene expression signature in expanded NK (ENK) cells and non-expanded NK cells isolated from healthy donors and myeloma patients. A specific set of genes involved in proliferation, migration, adhesion, cytotoxicity, and activation were up regulated post expansion, also confirmed by flow cytometry. Exp-NK cells killed both allogeneic and autologous primary MM cells more avidly than non-exp-NK cells in vitro. Multiple receptors, particularly NKG2D, natural cytotoxicity receptors, and DNAM-1 contributed to target lysis, via a perforin mediated mechanism. In summary, vigorous expansion and high anti-MM activity both in vitro and in vivo provide the rationale for testing exp-NK cells in a clinical trial for high risk MM. Differential gene expression profile in expanded natural killer (ENK) cells and non-expanded natural killer (NK) cells from healthy donors and myeloma patients Eight healthy donor and eight myeloma patients were used in the study. Non-expanded natural killer (NK) cells were isolated from PBMCs of healthy donors and myeloma patients. Expanded natural killer (ENK) cells were generated from same set of samples as mentioned in expansion protocol. All ENK and NK cells were used for gene expression profiling.
2011-03-08 | E-GEOD-27838 | biostudies-arrayexpress
Project description:Hepatocellular carcinoma (HCC) is frequently characterized by metabolic and immune remodeling in the tumor microenvironment. We previously discovered that liver-specific deletion of fructose-1, 6-bisphphotase 1 (FBP1), a gluconeogenic enzyme ubiquitously suppressed in HCC tissues, promotes liver tumorigenesis, and induces metabolic and immune perturbations closely resembling human HCC. However, the underlying mechanisms remain incompletely understood. Here we reported that FBP1-deficient livers exhibit diminished amounts of natural killer (NK) cells and accelerated tumorigenesis. Using the diethylnitrosamine-induced HCC mouse model, we analyzed potential changes in the immune cell populations purified from control and FBP1-depleted livers and found that NK cells were strongly suppressed. Mechanistically, FBP1 attenuation in hepatocytes derepresses an EZH2-dependent transcriptional program to inhibit PKLR expression. This leads to reduced levels of PKLR cargo proteins sorted into hepatocyte-derived EVs, dampened activity of EV-targeted NK cells, and accelerated liver tumorigenesis. Our study demonstrated that hepatic FBP1 depletion promotes HCC-associated immune remodeling, partly through the transfer of hepatocyte-secreted, PKLR-attenuated EVs to NK cells.
2023-03-11 | PXD026822 | Pride
Project description:<p>Natural killer (NK) cells are forced to cope with different oxygen environments even under resting conditions. The adaptation to low oxygen is regulated by oxygen-sensitive transcription factors, the hypoxia-inducible factors (HIFs). The function of HIFs for NK cell activation and metabolic rewiring remains controversial. Activated NK cells are predominantly glycolytic, but the metabolic programs that ensure the maintenance of resting NK cells are enigmatic. By combining <em>in situ</em> metabolomic and transcriptomic analyses in resting murine NK cells, our study defines HIF-1a as a regulator of tryptophan metabolism and cellular nicotinamide adenine dinucleotide (NAD+) levels. The HIF-1a/NAD+ axis prevents ROS production during oxidative phosphorylation (OxPhos) and thereby blocks DNA damage and NK cell apoptosis under steadystate conditions. In contrast, in activated NK cells under hypoxia, HIF-1a is required for glycolysis, and forced HIF-1a expression boosts glycolysis and NK cell performance <em>in vitro</em> and <em>in vivo</em>. Our data highlight two distinct pathways by which HIF-1a interferes with NK cell metabolism. While HIF-1a-driven glycolysis is essential for NK cell activation, resting NK cell homeostasis relies on HIF-1a-dependent tryptophan/NAD+ metabolism.</p><p><br></p><p><strong>Linked cross omic data sets:</strong></p><p>RNA-seq data associated with this study are available in ArrayExpress (BioStudies): accession <a href='https://www.ebi.ac.uk/biostudies/arrayexpress/studies/E-MTAB-12082' rel='noopener noreferrer' target='_blank'>E-MTAB-12082</a>.</p>
2023-06-01 | MTBLS6863 | MetaboLights
Project description:Natural killer (NK) cells are innate lymphocytes important for early host defense against infectious pathogens and surveillance against malignant transformation. Resting murine NK cells regulate the translation of effector molecule mRNAs (e.g. granzyme B, GzmB) through unclear molecular mechanisms. MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate the translation of their mRNA targets, and are therefore candidates mediating this control process. While the expression and importance of miRNAs in T and B lymphocytes has been established, little is known about miRNAs in NK cells. Here, we utilized two next-generation sequencing (NGS) platforms to define the miRNA transcriptomes of resting and cytokine-activated primary murine NK cells, with confirmation by RT-qPCR and microarrays. We delineate a bioinformatics analysis pipeline that identified 302 known and 28 novel mature miRNAs from sequences obtained from NK cell small RNA libraries. These miRNAs are expressed over a broad range, exhibit isomiR complexity, and a subset is differentially expressed following cytokine-activation. Using this miRNA NGS data, miR-223 was identified as a mature miRNA present in resting NK cells with decreased expression following cytokine-activation. Further, we demonstrate that miR-223 specifically targets the 3’UTR of murine GzmB in vitro, indicating that this miRNA may contribute to control of GzmB translation in resting NK cells. Thus, the sequenced NK cell miRNA transcriptome provides a valuable framework for further elucidation of miRNA expression and function in NK cell biology. Illumina GA (SRR036363, SRR036364) and SOLiD (SRR036206, SRR036210) sequencing data have been submitted to the NCBI Sequence Read Archive (SRA). The study uses a custome made array to characterize miRNA of activated and resting murine splenic natural killer cells
2010-10-01 | E-GEOD-21003 | biostudies-arrayexpress
Project description:Analysis of mouse primary natural killer (NK) cells and NK cells treated with DKK2 for 24 hours.Sequencing of the mRNAs from DKK2-treated primary NK cells in comparison of those from mock-treated cells suggest an alteration in STAT signaling.
2018-02-02 | GSE100402 | GEO
Project description:We performed a comprehensive genome-wide miRNA expression profiling (MEP) of extranodal nasal-type Natural Killer/T-cell lymphoma (NKTL) using formalin fixed paraffin-embedded tissue (FFPE) (n=30) and NK cell lines (n=6) in comparison with normal NK cells, with the objective of understanding the pathogenetic role of miRNA deregulation in NKTL. Total RNA, including miRNA, were extracted using Ambion Recoverall Kit and profiled using Agilent human miRNA V2.
2011-11-23 | E-GEOD-31377 | biostudies-arrayexpress