Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Genome-wide Screens Identify Lineage- and Tumor-Specific Genes Modulating MHC-I- and MHC-II-Restricted Immunosurveillance of Human Lymphomas [DLBCL_RNAseq]

ABSTRACT: Tumors frequently subvert MHC class I (MHC-I) peptide presentation to evade CD8+ T cell immunosurveillance, though how this is accomplished is not always well-defined. To identify the global regulatory networks controlling antigen presentation, we employed genome-wide screening in human diffuse large B cell lymphomas (DLBCLs). This approach revealed dozens of genes that positively and negatively modulate MHC-I cell surface expression. Validated genes clustered in multiple pathways including cytokine signaling, mRNA processing, endosomal trafficking, and protein metabolism. Genes can exhibit lymphoma subtype- or tumor-specific MHC-I regulation, and a majority of primary DLBCL tumors displayed genetic alterations in multiple regulators. We established SUGT1 as a major positive regulator of both MHC-I and MHC-II cell surface expression. Further, pharmacological inhibition of two negative regulators of antigen presentation, EZH2 and thymidylate synthase, enhanced DLBCL MHC-I presentation. These and other genes represent potential targets for manipulating MHC-I immunosurveillance in cancers, infectious diseases, and autoimmunity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160608 | GEO | 2020/11/02

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Genome-wide Screens Identify Lineage- and Tumor-Specific Genes Modulating MHC-I- and MHC-II-Restricted Immunosurveillance of Human Lymphomas [DLBCL_GSK126]

Project description:Tumors frequently subvert MHC class I (MHC-I) peptide presentation to evade CD8+ T cell immunosurveillance, though how this is accomplished is not always well-defined. To identify the global regulatory networks controlling antigen presentation, we employed genome-wide screening in human diffuse large B cell lymphomas (DLBCLs). This approach revealed dozens of genes that positively and negatively modulate MHC-I cell surface expression. Validated genes clustered in multiple pathways including cytokine signaling, mRNA processing, endosomal trafficking, and protein metabolism. Genes can exhibit lymphoma subtype- or tumor-specific MHC-I regulation, and a majority of primary DLBCL tumors displayed genetic alterations in multiple regulators. We established SUGT1 as a major positive regulator of both MHC-I and MHC-II cell surface expression. Further, pharmacological inhibition of two negative regulators of antigen presentation, EZH2 and thymidylate synthase, enhanced DLBCL MHC-I presentation. These and other genes represent potential targets for manipulating MHC-I immunosurveillance in cancers, infectious diseases, and autoimmunity.

2020-11-02 | GSE160609 | GEO

Ribosomal Proteins Regulate MHC Class I Peptide Generation for Immunosurveillance

Project description:The MHC class I antigen presentation system enables T cell immunosurveillance of cancers and viruses. Rapidly degraded nascent polypeptides (DRiPs) provide many class I peptide ligands. By knocking down each of the 80 ribosomal proteins, we identified proteins that modulate peptide generation without altering source protein expression. We show that 60S ribosomal proteins L6 (RPL6) and RPL28, which are adjacent on the ribosome, play opposite roles in generating an influenza A virus encoded peptide. RPL6 depletion decreases ubiquitin-dependent peptide presentation, while RPL28 depletion increases ubiquitin-dependent and -independent peptide presentation. 40S ribosomal protein S28 (RPS28) knockdown increases total peptide supply in uninfected cells by increasing DRiP synthesis from non-canonical translation of “untranslated” regions and non-AUG start codons, and sensitizes tumor cells for T cell targeting. RPL23 knocKDut decreases overall peptide supply, impairing T cell recognition of tumor cells. Our findings raise the possibility of modulating immunosurveillance by pharmacologically targeting ribosomes.

2019-01-21 | GSE114484 | GEO

Ribosomal Proteins Regulate MHC Class I Peptide Generation for Immunosurveillance

Project description:Ribosomal Proteins Regulate MHC Class I Peptide Generation for Immunosurveillance

| PRJNA471521 | ENA

Features of TAP independently presented MHC ligands revealed by quantitative mass spectrometry.

Project description:The TAP transporter is responsible for transferring cytosolic peptides into the ER where they can be loaded onto MHC molecules. Deletion of TAP results in a drastic reduction of MHC surface expression and alters the presented peptide pattern. Using the TAP deficient cell line LCL721.174 and its TAP expressing progenitor cell line LCL721.45, we have identified and quantified more than 160 HLA ligands, 50 out of which were presented TAP independently. Peptides which were predominantly presented on the TAP deficient LCL721.174 cell line had a decreased MHC binding affinity according to their SYFPEITHI and BIMAS score. About half of the identified TAP independently presented peptides were not derived from signal sequences and may partly be generated by the proteasome. Furthermore, we have excluded that different HLA presentation ratios were due to varying expression of the respective protein or due to changes in the antigen loading complex. Features of TAP-independently presented peptides as well as proteasomal contribution to their generation provides an insight into basic immunological mechanisms. Keywords: differential mass spectrometry, TAP independent, antigen presentation

2007-10-27 | GSE9437 | GEO

KDM5A epigenetically orchestrates MHC-I associated anti-tumor immunity of immunotherapy [DC RNA-seq]

Project description:Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but many patients with impaired MHC-I expression remain refractory. Histone methylation was involved in anti-tumor immunity of ICB. However, the link between histone methylation and MHC-I regulation and the related mechanisms are poorly understood. Here we show that KDM5A, an H3K4 demethylase that is critical for MHC-I expression and associated antigen presentation capacity, induces robust immune response and enhances ICB efficacy. Mechanistically, KDM5A upregulates IFN-gamma/STAT1-mediated MHC-I expression via directly binding and suppressing Scos1 in tumor cells. The genes encoding the lysosomal cathepsins are recognized and up-regulated by KDM5A, resulting in enhanced antigen-presentation abilities of both tumor cells and dendritic cells. Furthermore, pharmacological enhancing KDM5A improves response to anti-PD-1 therapy. These investigations demonstrate that enhancing KDM5A triggers MHC-associated antigen presentation of both tumor cells and DCs simultaneously to boost antitumor immunity, thus represents a candidate ICB sensitizer.

2024-03-31 | GSE260912 | GEO

Immunopeptidomics reveals determinants of Mycobacterium tuberculosis antigen presentation on MHC class I (SureQuant data)

Project description:CD8+ T cells contribute to protective immunity to Mycobacterium tuberculosis (Mtb), but the principles that govern presentation of Mtb peptides on MHC class I (MHC-I) on the surface of infected macrophages for CD8+ T cell recognition are incompletely understood. Here, we use internal standard parallel reaction monitoring (IS-PRM, also known as SureQuant) to rigorously validate identifications of Mtb-derived MHC-I peptides obtained in data-dependent MS analyses. We further use SureQuant to quantify presentation of Mtb peptides derived from the secreted effector proteins EsxA and EsxJ across multiple experimental conditions. We show that presentation of both EsxA- and EsxJ-derived peptides requires the activity of the mycobacterial ESX-1 type VII secretion system, possibly indicating that ESX-1-mediated phagosome membrane damage allows Mtb proteins to access MHC-I antigen processing pathways. We show that this requirement is independent of type I interferon signaling that occurs downstream of phagosome damage. Treatment with inhibitors of conventional proteolytic pathways involved in MHC-I antigen processing inhibits presentation of self peptides as expected, but does not inhibit presentation of Mtb peptides, implying an alternative or redundant mechanism of processing.

2023-04-24 | PXD037843 | Pride

Transcription profiling of mouse dendritic subsets in vivo

Project description:Dendritic cells (DCs) process and present self and foreign antigens to induce tolerance or immunity. In vitro models suggest that induction of immunity is controlled by regulating the presentation of antigen, but little is known about how DCs control antigen presentation in vivo. To examine antigen processing and presentation in vivo we specifically targeted antigens to the two major subsets of DCs using chimeric monoclonal antibodies. Unlike CD8+ DCs that express the cell surface protein CD205, CD8- DCs, which are positive for the 33D1 antigen, are specialized for presentation on MHC class II. This difference in antigen processing is intrinsic to the DC subsets and associated with increased expression of proteins associated with MHC processing. Experiment Overall Design: This study includes data from cell sort purified dendritic cells, B cells and CD4 and CD8 T cells. The genearray was performed to identify the transmembrane molecule recognized by the antibody 33D1. The antibody 33D1 binds specifically to CD8-CD11cHigh DCs in the spleen. Therfore the data set was reduced in this way that all molecules that are expressed either in CD8=CD11cHigh DCs, B cells and T cells were diminished of the CD8+CD11cHigh DC data set. This Genearray was also used to analyze MHC class I and MHC class II associated moelcules as the DC subsets differ in the antigen presentation. Each Series consists of 3 individuall samples

2008-06-14 | E-GEOD-6259 | biostudies-arrayexpress

Multiplexed relative and absolute quantitative immunpeptidomics reveals MHC I repertoire alterations induced by CDK4/6 inhibition [I]

Project description:Major histocompatibility complex (MHC) class I peptides play a critical role in immune cell recognition. Cancer cells modulate surface MHC levels in response to therapy, thereby affecting antitumor immunity. However, understanding the peptide repertoire response to treatment remains challenging and is limited by quantitative mass spectrometry-based strategies lacking robust normalization controls. We describe a novel approach that leverages recombinant heavy isotope-coded peptide MHCs (hipMHCs) and multiplex isotope tagging for quantitation of peptide repertoires using low sample input. HipMHCs improve quantitative accuracy by normalizing for variation across analyses, and enable absolute quantification using internal calibrants to determine copies per cell of MHC antigens. Application of this platform to profile the immunopeptidome response to CDK4/6 inhibition and Interferon gamma, known modulators of antigen presentation, uncovered treatment-specific alterations that connect the intracellular response to extracellular immune presentation. This method quantifies repertoire changes that can inform targeted and combination immunotherapy design.

2020-04-29 | GSE144373 | GEO

Activated SUMOylation restricts the MHC class I antigen presentation pathway to confer immune evasion in cancer

Project description:Activated SUMOylation is a hallmark of aggressive cancers. Starting from a targeted screening for SUMO-regulated immune evasion mechanisms, we identified an evolutionary conserved function of activated SUMOylation, which attenuates the immunogenicity of tumor cells. Activated SUMOylation allows cancer cells to evade CD8+ T-cell immunosurveillance by repressing the MHC-I antigen processing and presentation machinery (APM). While loss of the MHC-I APM is a frequent cause of resistance to cancer immunotherapies, the pharmacological inhibition of SUMOylation (SUMOi) restored the expression of the MHC-I APM and enhanced the susceptibility of tumor cells to CD8+ T-cell mediated killing. Importantly, SUMOi also triggered the activation of CD8+ T-cells itself and thereby drives a feed-forward loop amplifying the specific anti-tumor immune response. In summary, we show that activated SUMOylation converts tumor cells into a state of immune evasion, and identify SUMOi as rational therapeutic strategy for enhancing the efficacy of cancer immunotherapies.

2022-01-15 | PXD030506 | Pride

Viral immune evasions differentially impact cell surface presentation of MHC I allomorphs already at the peptide-loading complex

Project description:The transporter associated with antigen processing (TAP) translocates peptides from the cytosol into the endoplasmic reticulum (ER) where they are loaded onto major histocompatibility class I (MHC I) molecules. Stable peptide-MHC I complexes travel to the cell surface and present their antigenic cargo to cytotoxic T lymphocytes. As central part of the peptide-loading complex (PLC), TAP is targeted by several viral proteins, which inhibit peptide translocation and thereby impact MHC I-mediated immune responses. However, it is still poorly understood whether the MHC I allotypes are differently affected by TAP inhibition. Here, we show that conditional expression of herpes simplex virus (HSV) ICP47 suppresses surface presentation of the MHC I allotypes HLA-A and HLA-C, but not of HLA-B, while expression of cytomegalovirus (CMV) US6 reduces surface levels of all allotypes. This difference is directly reflected in a specific enrichment of HLA-B molecules at US6 arrested PLC. Since ICP47 and US6 inhibit TAP in different transport-incompetent conformations, our data imply that MHC I allomorphs are preferentially recruited or trapped at the PLC leading to selective downregulation of MHC I surface presentation. Our findings suggest that viral immune evasions not only inhibit peptide supply to the ER by TAP, but also modulate the assembly and chaperone activity of the PLC.

2022-02-17 | PXD027408 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data