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Multi-phenotype CRISPR-Cas9 screen identifies p38 kinase as a target for adoptive immunotherapies

ABSTRACT: Multi-phenotype CRISPR-Cas9 screen identifies p38 kinase as a target for adoptive immunotherapies

PROVIDER: PRJNA464286 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7126100_1.fastq.gz	Fastqsanger.gz
	SRR7126100_2.fastq.gz	Fastqsanger.gz
	SRR7126101_1.fastq.gz	Fastqsanger.gz
	SRR7126101_2.fastq.gz	Fastqsanger.gz
	SRR7126102_1.fastq.gz	Fastqsanger.gz

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Multi-phenotype CRISPR-Cas9 screen identifies p38 kinase as a target for adoptive immunotherapies

Project description:T cells are central to all currently effective cancer immunotherapies, but the characteristics defining therapeutically effective anti-tumor T cells have not been comprehensively elucidated. Here we delineate four phenotypic qualities of effective anti-tumor T cells: cell expansion, differentiation, oxidative stress, and genomic stress. Using a CRISPR-Cas9-based genetic screen of primary T cells we measured the multi-phenotypic impact of disrupting 25 T cell receptor driven kinases. We identified p38 kinase as a central regulator of all four phenotypes and uncovered transcriptional and antioxidant pathways regulated by p38 in T cells. Pharmacological inhibition of p38 improved the efficacy of mouse anti-tumor T cells and enhanced the functionalities of human tumor-reactive and gene-engineered T cells, paving the way for clinically relevant interventions.

2020-06-09 | GSE114087 | GEO

Expression profiling, U2OS, Aurora kinase and p38 inhibitor response

Project description:U-2 OS (human osteosarcoma cell line) were treated with ZM447439 (an aurora kinase inhibitor), SB202190 (a p38 inhibitor) or ZM447439+SB202190 and resulting changes in gene expression were profiled.

2017-07-01 | E-MTAB-1210 | biostudies-arrayexpress

Weizmannia coagulans P38

Project description:BACILLUS-COAGULANS-P38

| PRJNA218161 | ENA

C-type natriuretic peptide regulates endochondral ossification through p38 MAP kinase-dependent pathways_2

Project description:C-type natriuretic peptide (CNP) has been recently identified as an important anabolic regulator of endochondral bone growth, but the molecular mechanism mediating these effects are not completely understood. Here we demonstrate that CNP activates the p38 MAP kinase pathway in chondrocytes and that pharmacological inhibition of p38 blocks the anabolic effects of CNP in a tibia organ culture system. We further show that CNP stimulates endochondral bone growth largely through expansion of the hypertrophic zone of the growth plate, while delaying mineralization. Both effects are reversed by p38 inhibition. We performed Affymetrix microarray analyses to identify CNP target genes in the organ culture system. These studies confirmed that hypertrophic chondrocytes are the main targets of CNP signaling in the growth plate, potentially because cGMP-dependent kinases I and II, important transducers of CNP signaling and are expressed at much higher levels in these cells than in other areas of the tibia. One of the genes most strongly induced by CNP was the Ptgs2 gene, encoding Cox2. Real-time PCR confirmed that Cox2 expression was induced by CNP in hypertrophic chondrocytes, but surprisingly in a p38-independent manner. Moreover, Cox2 inhibition – in contrast to p38 inhibition - did not block the anabolic effects of CNP. In summary, our data identify novel target genes of CNP and demonstrate that the p38 pathway is a novel, essential mediator of CNP effects on endochondral ossification, with potential implications for numerous skeletal diseases. Keywords: Growth plate zone comparison and treatment response analysis

2006-12-15 | GSE4481 | GEO

Transcription profiling by array of left ventricle tissues from rat with overexpression of constitutively active upstream kinase mitogen-activated protein kinase kinase 3b (MKK3bE) and wild-type p38? in the heart

Project description:Mitogen-activated protein kinases (MAPKs) regulate cardiomyocyte growth and apoptosis in response to extracellular stimulation, but the downstream effectors that mediate their pathophysiological effects remain poorly understood. We determined the targets and role of p38 MAPK in the heart in vivo by using local adenovirus-mediated gene transfer of constitutively active upstream kinase mitogen-activated protein kinase kinase 3b (MKK3bE) and wild-type p38Î± in rats. DNA microarray analysis of animals with cardiac-specific overexpression of p38 MAPK revealed that 264 genes were upregulated more than 2-fold including multiple genes controlling cell division, cell signaling, inflammation, adhesion and transcription. Several previously unknown p38 target genes were found. Using gel mobility shift assays we identified several cardiac transcription factors that were directly activated by p38 MAPK. Finally, we determined the functional significance of the altered cardiac gene expression profile by histological analysis and echocardiographic measurements, which indicated that p38 MAPK overexpression induced gene expression results in cell proliferation, myocardial inflammation and fibrosis. In conclusion, we defined the novel target genes and transcription factors as well as the functional effects of p38 MAPK in the heart. Expression profiling of p38 MAPK overexpression identified cell cycle regulatory and inflammatory genes critical for pathological processes in the adult heart. Experiment Overall Design: Left ventricular gene expression profiles three days after MKK3bE + WT p38Î± gene transfer were compared with those of Lac Z âtreated animals by screening Affymetrix Rat Expression Set 230_2.0 Arrays (there are 5 samples in both group).

2009-04-25 | E-GEOD-3866 | biostudies-arrayexpress

Inhibition of PARP11 inactivates tumor-infiltrating regulatory T cells and improves the efficacy of immunotherapies.

Project description:Tumor-infiltrating regulatory T cells (TI-Tregs) elicit immunosuppressive effects in the tumor microenviroment (TME) leading to accelerated tumor growth and resistance to immunotherapies against solid tumors. Here we demonstrate that Poly-(ADP-ribose)-polymerase-11 (PARP11) acts as an essential regulator of TI-Tregs regulatory and protumorigenic activities. Expression of PARP11 correlated with TI-Treg infiltration and poor responses to immune checkpoint blockade (ICB) in human cancer patients. PARP11 was induced in the TI-Treg cells by tumor-derived factors including adenosine and prostaglandin E2. Knockout of PARP11 in the cells of the TME or treatment of tumor-bearing mice with selective PARP11 inhibitor ITK7 inactivated TI-Treg cells and reinvigorated anti-tumor immune responses. Accordingly, ITK7 decelerated tumor growth and significantly increased the efficacy of anti-tumor immunotherapies including ICB and adoptive transfer of CAR T cells. These results characterize PARP11 as a key driver of TI-Treg activities and a major regulator of immunosuppressive TME and argue for targeting PARP11 to augment anti-cancer immunotherapies.

2023-12-07 | GSE249299 | GEO

Casirati et al. Epitope Editing of Hematopoietic Stem Cells

Project description:Data for the manuscript Casirati et al. "Epitope Editing of Hematopoietic Stem Cells Enables Adoptive Immunotherapies for Acute Myeloid Leukemia"

2023-06-26 | MSV000092272 | MassIVE

Receptor Tyrosine Kinase Inhibitors Block proliferation of coronavirus mainly through p38 mitogen-activated protein kinase pathways

Project description:Emerging coronaviruses (CoVs) primarily cause severe gastroenteric or respiratory diseases in humans and animals, for which no approved therapeutics are available so far. Here A9, a receptor tyrosine kinase inhibitors (RTKIs) of the tyrphostin class was identified as a robust inhibitor of TGEV (Transmissible gastroenteritis virus) infection in cell-based assays. Time-of-addition studies suggested that A9 mainly acts at post-adsorption stage of the TGEV life cycle. Moreover, it also exhibited potent antiviral activity against various coronavirus replication, including MHV, PEDV and FIPV. We further investigated the mechanism of action of A9 against TGEV infection in vitro with comparative phosphoproteomics analysis. We specifically identified the A9 target, p38 and JNK1, the downstream molecules of receptor tyrosine kinases (RTKs) as required for efficient TGEV replication in vitro through plaque assay, qRT-PCR and western blotting assays. Additionally, tests of p38 and JNK1 inhibitors also indicated that interventions targeting p38 was more effective in suppressing TGEV propagation than the JNK. In conclusion, these findings indicate that the receptor tyrosine kinase inhibitor A9 can directly inhibits TGEV replication and its inhibitory activity on TGEV replication mainly regulated by targeting p38, which provide vital clues to design novel drugs against coronavirus.

2020-05-26 | PXD010685 | Pride

Adoptive cell therapy [Fig.4]

Project description:Adoptive cell therapy [Fig.4]

| PRJNA821483 | ENA

Bacillus sp. P38

Project description:Bacillus sp. P38 Transcriptome or Gene expression

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