Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

EHMT1/2 knockout induces a broad interferon signature

ABSTRACT: Epigenetic silencing of interferon (IFN) signaling contributes to the profound resistance of “immune-cold” tumors to PD-1/PD-L1 blockade. In this study, we conducted a fluorescence-activated cell sorting (FACS)-based CRISPR-Cas9 screen to identify tumor-intrinsic regulators of PD-L1 surface expression and identified the histone-lysine methyltransferases EHMT1 and EHMT2 as key suppressors of interferon signaling. We then developed TNG917, a histone substrate-competitive dual inhibitor of EHMT1/2 with superior, low-nanomolar potency in cells and high selectivity over other methyl transferases. In cancer cell lines, TNG917 relieved H3K9-mediated repression, restored interferon-stimulated gene expression, and triggered secretion of T-cell chemoattractant cytokines including CXCL10. When dosed orally in both syngeneic and humanized mouse models, TNG917 monotherapy led to marked tumor growth inhibition, while combination with anti-PD1 therapy produced complete, durable regressions and established protective immune memory. Early pharmacokinetic and toxicology assessments revealed favorable exposure profiles and a wide safety margin. These findings establish EHMT1/2 inhibition by TNG917 as a novel strategy to convert immune-cold tumors into T-cell-inflamed lesions and potentiate checkpoint blockade, supporting its advancement into clinical development in combination immunotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE333664 | GEO | 2026/06/08

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Tumor PD-L1 engages myeloid PD-1 to suppress type I interferon to impair cytotoxic T lymphocyte recruitment (single cells)

Project description:A hallmark of PD-1/L1 blockade is long-term, sustained remission of metastatic disease. How the immune system coordinates the destruction of macro- and micro-metastases following checkpoint blockade, however, remains unclear. Here, we show that tumor-expressed PD-L1 (tPD-L1) enhanced metastasis in a mechanism distinct from and independent of its role in primary tumor growth. This difference in metastatic growth was mediated by cytotoxic T lymphocytes (CTLs), however, tPD-L1 did not promote effector CTL exhaustion or suppress lytic activity in vivo. Instead, single cell RNA sequencing revealed that tPD-L1 engaged macrophage-expressed PD-1 to antagonize type I interferon production and signaling, creating an immunologically ‘cold’ microenvironment. Loss of tPD-L1 eliminated metastases by driving interferon-mediated sensitization of tumor cells to CTL lysis and CTL recruitment.

2023-02-06 | GSE150742 | GEO

Tumor PD-L1 engages myeloid PD-1 to suppress type I interferon to impair cytotoxic T lymphocyte recruitment (bulk)

2023-02-06 | GSE150739 | GEO

Expression of Data from EHMT1 siRNA transfected HeLa cell treated with TNF

Project description:We used microarrays to detail the global programme of gene expression to identify TNF-induced genes that are negatively regulated by EHMT1 Transcriptional homeostasis relies on the balance between positive and negative regulation of gene transcription. Methylation of histone H3 lysine 9 (H3K9) is commonly correlated with gene repression. Here, we report that a euchromatic H3K9 methyltransferase, EHTM1, functions as a negative regulator in both the NF-?B- and type I interferon-mediated gene induction pathways. EHMT1 catalyzes H3K9 methylation at promoters of NF-?B target genes. Moreover, EHMT1 interacts with p50 and, surprisingly, p50 appears to repress the expression of type I interferon genes and genes activated by type I interferons by recruiting EHMT1 to catalyze H3K9 methylation at their promoter regions. Silencing the expression of EHMT1 by RNA interference enhances expression of a subset NF-?B regulated genes, augments interferon production and augments antiviral immunity. HeLa cells were double-transfected with control or EHMT1 specific siRNAs. The cells were then treated with or without TNFa for 2 hours followed by RNA extraction and hybridization on Affymetrix microarrays.

2012-07-30 | E-GEOD-39744 | biostudies-arrayexpress

Epigenetic repression of STING by MYC promotes immune evasion and resistance to immune checkpoint inhibitors in triple negative breast cancer [CHIP-seq]

Project description:The MYC oncogene is frequently amplified in triple negative breast cancer (TNBC). Here, we show that MYC suppression induces immune-related hallmark gene set signatures and tumor infiltrating T cells in MYC-hyperactivated TNBCs. Mechanistically, MYC repressed stimulator of interferon genes (STING) expression via direct binding to the STING enhancer region, resulting in downregulation of the T cell chemokines CCL5, CXCL10 and CXCL11. In primary and metastatic TNBC cohorts, tumors with high MYC expression or activity exhibited low STING expression. Using a CRISPR-mediated enhancer perturbation approach, we demonstrated that MYC-driven immune evasion is mediated by STING repression. STING repression induced resistance to PD-L1 blockade in mouse models of TNBC. Finally, a small molecule inhibitor of MYC combined with PD-L1 blockade elicited a durable response in immune-cold TNBC with high MYC levels, suggesting a strategy to restore PD-L1 inhibitor sensitivity in MYC-overexpressing TNBC.

2022-03-01 | GSE196324 | GEO

Epigenetic repression of STING by MYC promotes immune evasion and resistance to immune checkpoint inhibitors in triple negative breast cancer [RNA-seq]

2022-03-01 | GSE196323 | GEO

PD-1/CD80+ small extracellular vesicles from immunocytes induce cold tumours featuring with enhanced adaptive immunosuppression

Project description:Only a minority of cancer patients benefit from immune checkpoint blockade therapy. Sophisticated cross-talk among different immune checkpoint pathways as well as interaction pattern of immune checkpoint molecules carried on circulating small extracellular vesicles (sEV) might contribute to the low response rate. Here we demonstrate that PD-1 and CD80 carried on immunocyte-derived sEVs (I-sEV) induce an adaptive redistribution of PD-L1 in tumour cells. The resulting decreased cell membrane PD-L1 expression and increased sEV PD-L1 secretion into the circulation contribute to systemic immunosuppression. PD-1/CD80+ I-sEVs also induce downregulation of adhesion- and antigen presentation-related molecules on tumour cells and impaired immune cell infiltration, thereby converting tumours to an immunologically cold phenotype. Moreover, synchronous analysis of multiple checkpoint molecules, including PD-1, CD80 and PD-L1, on circulating sEVs distinguishes clinical responders from those patients who poorly respond to anti-PD-1 treatment. Altogether, our study shows that sEVs carry multiple inhibitory immune checkpoints proteins, which form a potentially targetable adaptive loop to suppress antitumour immunity.

2024-06-22 | PXD050744 | Pride

Soluble immune-checkpoint factors as a complementary biomarker for PD-1 blockade reflect exhaustion of antitumor immunity

Project description:BACKGROUND. Precise stratification of patients with non–small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy. METHODS. We measured soluble (s) forms of the PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. Prospective biomarker finding trial (cohort A), 50 patients with pretreated NSCLC received nivolumab. In cohort B to E, retrospective observational study, soluble immune checkpoint molecules were evaluated for patients with advanced NSCLC treated with any PD-1/PD-L1 blockade (cohort B and C), cytotoxic chemotherapy (D) or targeted therapy (E). Blood samples were obtained from all patients and soluble immune checkpoint molecules were evaluated using a highly sensitive chemiluminescence-based assay. RESULTS. Nonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such correlation was not observed in patients treated with cytotoxic chemotherapy or targeted therapies. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the three soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of sPD-L1 and sCTLA-4 efficiently discriminated responsiveness among patients with immune-reactive tumors. CONCLUSION. Combinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest such a combination might provide a biomarker complementary to tPD-L1 for NSCLC patients.

2024-03-30 | GSE242860 | GEO

All-trans retinoic acid destabilizes ADAR1 protein through retinoylation-mediated USP7 dissociation and improves immunotherapy in pancreatic cancer

Project description:ADAR1-p150 isoform, an interferon-stimulated double-stranded RNA-editing enzyme, contributes to immunotherapy resistance by suppressing interferon signaling. While genetic depletion of ADAR1 overcomes immunotherapy resistance in preclinical models, therapeutic targeting of ADAR1 has not been achieved to date in clinical setting. In this study, we found that the FDA-approved all-trans retinoic acid (ATRA) promoted ADAR1 protein degradation in different types of cancer. In addition, ATRA also induces the transcription of PD-L1 in cancer cells and the combination of ATRA and PD-1 blockade reprogrammed the tumor microenvironment to unleash antitumor immunity, thereby impeding tumor growth in vivo. Mechanistically, we identified deubiquitinase USP7 as a key regulator for ADAR1 protein stability. ATRA disrupts the USP7-ADAR1 interaction, promoting ADAR1 degradation. Notably, the regulation of ADAR1 protein degradation by ATRA is independent of its canonical receptors. Instead, ATRA treatment leads to ADAR1 retinoylation, a post-translational modification by conjugation of retinoids, which results in the disruption of USP7-ADAR1 complex to promote ADAR1polyubiquitination. Importantly, clinical data shows a positive correlation between USP7 and ADAR1 protein expression in various cancers, supporting USP7's role in ADAR1 stabilization. Overall, this study sheds light on the control of ADAR1 protein turnover and proposes a mechanism-driven combination therapy using ATRA and PD-1/PD-L1 blockade to convert immunologically cold into hot tumors, holding potential for clinical translation.

2025-07-19 | MSV000098564 | MassIVE

Transcriptomic analysis of PD-L1 positive and negative hot lung adenocarcinomas identifies a different molecular immunogenic landscape

Project description:Lung cancer is a major global health problem, as it is the leading cause of cancer- related deaths worldwide. Non-small-cell lung cancer (NSCLC), the most common form, is a heterogeneous disease with adenocarcinoma and squamous cell carcinoma being the predominant subtypes. Immune-inhibiting interaction of Programmed cell death-ligand 1 (PD-L1) with programmed cell death-protein 1 (PD-1) causes checkpoint mediated immune evasion and is, accordingly, an important therapeutic target in cancer. In NSCLC, improved understanding of PD-1/PD-L1 checkpoint blockade-responsive biology is warranted. We aimed to identify the landscape of immune cell infiltration in primary lung adeno- carcinoma (LUAD) in the context of tumor PD-L1 expression and the extent of immune infiltration (“hot” vs. “cold” phenotype). Therefore, the study comprises LUAD cases (n=138) with “hot” and “cold” tumor immune phenotype and positive and negative tumor PD-L1 expression, respectively. Tumor samples were immunohistochemically analyzed for expression of PD-L1, CD4 and CD8 and further analyzed on transcriptomic level by Nanostring nCouter Pan Cancer Immune Profiling Panel. We detected significantly differentially expressed genes associated with PD-L1 positive and “hot” versus PD-L1 negative and “cold” phenotype. The presented study illustrates novel aspects of PD-L1 regulation, with potential biological relevance, as well as relevance for immunotherapy response stratification.

2021-09-27 | GSE180347 | GEO

Cell surface interactome analysis identifies TSPAN4 as a negative regulator of PD-L1 in melanoma

Project description:PD-L1 functions as a co-inhibitory checkpoint ligand constraining anti-tumor immunity by binding to PD-1 on immune cells. Although antibody blockade therapy displays clear therapeutic responses, it is not effective in all cancer patients, indicating modulation by other factors. We applied cell surface proximity biotinylation combined with mass spectrometry in melanoma cells to identify novel proteins regulating PD-L1 function. Our findings reveal that membrane organizing protein Tetraspanin-4 (TSPAN4) interacts with PD-L1, where both proteins colocalize on migrasomes and retraction fibers. We demonstrate that TSPAN4 negatively affects PD-L1 protein levels and inhibits PD-L1 lateral mobility on the plasma membrane. TSPAN4 knockdown results in a reduced PD-L1 degradation rate, and enhanced PD-L1 interaction with CMTM6 as the molecular mechanism. Consequently, increased PD-L1 levels in TSPAN4 knockdown melanoma cells leads to enhanced PD-1 binding, and more efficient immune checkpoint blockade through inhibition of T cell responses. This study identifies TSPAN4 as a negative regulator of PD-L1 at the cell surface of melanoma cells, suggesting that TSPAN4 may represent a novel target for improving immune checkpoint therapy in cancer patients.

2026-01-16 | PXD064698 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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