Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

IFNγ treatment restores TAP-dependent presentation competence of PD-L1 sensitive PDAC cells

ABSTRACT: For immunotherapy, there is an urgent need to restore presentation-competence of cancer cells with defects in MHC-I processing/presentation. We identified two tumor-specific antigens expressed in the ER of pancreatic ductal adenocarcinoma cells (PDACCs) that induced effector CD8 T cells either independent (Cripto-1-Kb/Cr16-24) or dependent (gp70-Kb/p15E) on TAP-mediated antigen processing/presentation by DNA immunization. In systematic analyses, we showed that transplantation into syngeneic C57BL/6J mice or IFNγ-treatment in vitro upregulated MHC-I but also co-inhibitory PD-L1 molecules on PDACCs. IFNγ-treated PDACCs efficiently formed solid tumors in transplanted C57BL/6J and PD-L1-/- but were rejected in PD-1-/- mice. PDACCs induced a prophylactic immunity against tumor transplants in C57BL/6J mice when irradiated at day 2-3 post IFNγ-treatment, thereby silencing the tumor-initiated immune-suppressive PD-L1/PD-1-signaling axis. Immune-protection correlated with a significant enhanced induction of CD8 T cells against the TAP- but not the TAP-dependent antigen/epitope.

ORGANISM(S): Mus musculus

PROVIDER: GSE140397 | GEO | 2020/08/06

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

IFNγ treatment restores TAP-dependent presentation competence of PD-L1 sensitive PDAC cells

Project description:IFNγ treatment restores TAP-dependent presentation competence of PD-L1 sensitive PDAC cells

| PRJNA589595 | ENA

Epigenetic regulations in the IFNγ signalling pathway: IFNγ-mediated MHC class I upregulation on tumour cells is associated with DNA demethylation of antigen-presenting machinery genes [TC1A9_IFN]

Project description:Reversible MHC class I deficiency on tumour cells is commonly caused by coordinated silencing of antigen-presenting machinery genes and restorable by IFNγ. Here we describe association of DNA demethylation of selected antigen-presenting machinery gene regulatory regions located in the MHC genomic locus (TAP-1, TAP-2, LMP-2, LMP-7) upon IFNγ treatment with MHC class I upregulation on tumour cells. Our novel findings demonstrate that IFNγ acts as an epigenetic modifier upregulating the expression of antigen-presenting machinery genes through DNA demethylation. Our data also cast more light on the role of DNA methylation in tumour cell escape from specific immunity.

2014-12-08 | GSE53467 | GEO

Epigenetic regulations in the IFNγ signalling pathway: IFNγ-mediated MHC class I upregulation on tumour cells is associated with DNA demethylation of antigen-presenting machinery genes [TC1A9_DAC]

2014-12-08 | GSE53466 | GEO

Epigenetic regulations in the IFNγ signalling pathway: IFNγ-mediated MHC class I upregulation on tumour cells is associated with DNA demethylation of antigen-presenting machinery genes [RVPC3_DAC]

2014-12-08 | GSE53465 | GEO

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

Immune cells and their inflammatory mediators modify beta cells and cause checkpoint inhibitor-induced diabetes

Project description:Checkpoint inhibitors (CPIs) targeting PD-1/PD-L1 and CTLA-4 have revolutionized cancer treatment but can trigger autoimmune complications including CPI-induced diabetes (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti-PD-L1 but not anti-CTLA-4 induces DM rapidly. RNA sequencing revealed that cytolytic IFNγ+ CD8+ T cells infiltrated islets with anti-PD-L1. Changes in β cells were predominantly driven by IFNγ and TNFα and included induction of a novel β cell population with transcriptional changes suggesting dedifferentiation. IFNγ increased checkpoint ligand expression and activated apoptosis pathways in human β cells in vitro. Treatment with anti-IFNγ and anti-TNFα prevented CPI-DM in anti-PD-L1 treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway result in transcriptional changes in β cells and immune infiltrates that may lead to the development of diabetes. Inhibition of inflammatory cytokines can prevent CPI-DM, suggesting a strategy for clinical application to prevent this complication.

2022-10-27 | GSE208644 | GEO

Immune cells and their inflammatory mediators modify beta cells and cause checkpoint inhibitor-induced diabetes

2022-10-27 | GSE209587 | GEO

BCR repertoire profiling of murine ABC-DLBCL-like tumors [targeted RNA-seq]

Project description:We have developed a novel immunocompetent multi-lesion mouse model of activated B cell diffuse large B-cell lymphoma (ABC-DLBCL; the pBIC mice) that recapitulates relatively fast the molecular, cellular and tumor microenvironment of aggressive human ABC-DLBCL. We demonstrate that perturbed p53 signaling cooperates with constitutive NF-kB activation in GC-experienced plasmablasts with blocked terminal differentiation to promote lymphomagenesis and tumor progression through triggering downstream intracellular molecular addictions (e.g. deregulating Foxp1 and AID pathways) and intercellular immunosuppressive signals for evading anti-tumoral responses (e.g. MHC-II antigen presentation and deregulating PD-L1/PD-1 immune checkpoint). Our immunocompetent ABC-DLBCL murine model provides in vivo evidence that PD-1 blockade cooperates with anti-CD20-based current standard-of-care therapy to reshape the immunosuppressive TME and facilitate long-term anti-tumoral responses. Therefore, our results support that immune checkpoints may hold promising therapeutic potential in ABC-DLBCL.

2019-04-19 | GSE117119 | GEO

Transcriptional profiling of human OCI-Ly1 DLBCL cells after siRNA-mediated silencing of FOXP1 [array]

2019-04-19 | GSE116289 | GEO

Transcriptional profiling of murine ABC-DLBCL-like tumors [RNA-seq]

2019-04-19 | GSE116288 | GEO