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CHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity [CRISPR]

ABSTRACT: We report the application of a two-cell -type whole genome KO CRISPR screen to find new moecular targets that increase the sensitivity or resistance to NK cells cytotoxixity in glioblastoma stem cells and head and neck squamous cells carcinoma cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE175862 | GEO | 2021/06/02

REPOSITORIES: GEO

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CHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity [RNA-seq]

Project description:We report the application of a two-cell -type whole genome KO CRISPR screen to find new moecular targets that increase the sensitivity or resistance to NK cells cytotoxixity in glioblastoma stem cells and head and neck squamous cells carcinoma cells. Here we report the RNA sequencing for the CHMP2A KO glioblastoma stem cells CW468 and 387

2021-06-02 | GSE175863 | GEO

Novel non-canonical role of STAT1 in Natural Killer cell cytotoxicity

Project description:STAT1 is an important regulator of NK cell maturation and cytotoxicity. Although the consequences of Stat1-deficiency have been described in detail the underlying molecular functions of STAT1 in NK cells are only partially understood. Here we describe a novel non-canonical role of STAT1 that was unmasked in NK cells expressing Stat1-Y701F. This mutation prevents JAK-dependent phosphorylation, subsequent nuclear translocation and cytokine-induced transcriptional activity. As expected Stat1-Y701F mice displayed impaired NK cell maturation comparable to Stat1-/- animals. In contrast Stat1-Y701F NK cells exerted a significantly enhanced cytotoxicity in vitro and in vivo suggesting a so-far unknown cytoplasmic function. Using immunofluorescence technology we uncovered the recruitment of STAT1 to the immunological synapse during NK cell killing. A Stat1ind mouse expressing FLAG-tagged STAT1α was used to study the STAT1α interactome in NK cells. Mass spectrometry revealed that STAT1 directly binds proteins involved in cell junction formation and proteins associated to membrane or membrane-bound vesicles. We propose a novel function for STAT1 in the immunological synapse of NK cells regulating tumor surveillance and cytotoxicity.

2016-10-07 | PXD002206 | Pride

Mechanisms of Cancer Resistance to Immunogenic Cytotoxicity

Project description:The majority of cancer patients do not respond to immunotherapy. In order to systematically discover pathways promoting cancer cell resistance to effector immune cells, we generated immunity-resistant Head and Neck Squamous Cell Carcinoma cell lines. We utilized RNA-Seq to determine what are the genes and pathways that are significantly altered when cancer cells become resistant to effectors.

2018-12-25 | GSE100828 | GEO

Resting natural killer cell homeostasis relies on tryptophan/NAD+ metabolism and HIF-1α

Project description: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 in situ 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 in vitro and in vivo. 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. Linked cross omic data sets: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>.

2023-06-01 | MTBLS6863 | MetaboLights

CHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity.

Project description:Natural killer (NK) cells are known to mediate killing of various cancer types, but tumor cells can develop resistance mechanisms to escape NK cell-mediated killing. Here, we use a "two cell type" whole genome CRISPR-Cas9 screening system to discover key regulators of tumor sensitivity and resistance to NK cell-mediated cytotoxicity in human glioblastoma stem cells (GSC). We identify CHMP2A as a regulator of GSC resistance to NK cell-mediated cytotoxicity and we confirm these findings in a head and neck squamous cells carcinoma (HNSCC) model. We show that deletion of CHMP2A activates NF-κB in tumor cells to mediate increased chemokine secretion that promotes NK cell migration towards tumor cells. In the HNSCC model we demonstrate that CHMP2A mediates tumor resistance to NK cells via secretion of extracellular vesicles (EVs) that express MICA/B and TRAIL. These secreted ligands induce apoptosis of NK cells to inhibit their antitumor activity. To confirm these in vitro studies, we demonstrate that deletion of CHMP2A in CAL27 HNSCC cells leads to increased NK cell-mediated killing in a xenograft immunodeficient mouse model. These findings illustrate a mechanism of tumor immune escape through EVs secretion and identify inhibition of CHMP2A and related targets as opportunities to improve NK cell-mediated immunotherapy.

| S-EPMC8990014 | biostudies-literature

Gene expression profiles of head and neck squamous cell carcinoma

Project description:Sage performed on microdissection of Head and Neck tumor, and Head and Neck normal tissue comparative analysis of gene expression profiles of head and neck squamous cell carcinoma and Head and Neck normal tissue

2008-09-30 | E-GEOD-11986 | biostudies-arrayexpress

CHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-06-02 | GSE175864 | GEO

Gene expression analysis of head and neck squamous cell carcinoma cell lines and a control normal oral epithelial cell line

Project description:Microarrays were used to examine gene expression differences between human head and neck squamous cell carcinoma cell lines (FaDu, UTSCC8, UTSCC42a) grown in culture in comparison to a normal oral epithelial cell line. Gene expression data was integrated with global protein expression of head and neck squamous cell carcinoma cell lines and conditioned media to identify secreted protein markers up-regulated at the mRNA level in cancer cells versus the normal cell line. Total RNA obtained from head and neck squamous cell carcinoma cell lines and a normal oral epithelial cell line

2012-08-28 | E-GEOD-40185 | biostudies-arrayexpress

Analysis of microRNAs expression in four head and neck cancer cell lines

Project description:MicroRNA expression in two pair of head and neck squamous cell carcinoma cell lines were analyzed. 4A/4B and 37A/37B cells were from two different head and neck squamous cell carcinoma patients. A cells were from patients' primary focus. B cells were from patients' lymph node metastasis. B cells have higher migratory and invasive abilities and CCR7 expression levels than A cell.

2021-05-01 | GSE115000 | GEO

MethylationEPIC array from fresh oral and oropharyngeal tissue samples from head and neck squamous cell carcinoma patients, tissue samples from potentially premalignant oral lesions and fresh tonsil tissue samples from control patients

Project description:This data was used to detect good biomarkers for head and neck squamous cell carcinoma and was integrated with transcriptome and miRNome data aiming to elucidate role of epigenetics on gene expression in head and neck squamous cell carcinoma.

2024-04-22 | E-MTAB-13954 | biostudies-arrayexpress

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