Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

XRN1 knockdown in tumor cells stimulates immune cell infiltration

ABSTRACT: Despite the remarkable achievement of immune checkpoint blockade (ICB) therapy, the response rate is relatively low and only a subset of patients can benefit from the treatment. We hypothesize that targeting RNA decay machinery may lead to accumulation of aberrantRNA, triggering interferon (IFN) signaling and sensitizing tumor cells to immunotherapy. With this in mind, we identified an RNA exoribonuclease, XRN1 as a potential target. Silencing of XRN1 suppressed tumor growth in syngeneic immunocompetent mice and potentiated immunotherapy, while silencing of XRN1 alone did not affect tumor growth in immune deficient mice. Mechanistically, XRN1 depletion activated interferon signaling and viral defense pathway; both pathways play determinant roles in regulating immune evasion. In murine tumors engrafted on immmunocompetent mice, XRN1 depletion significantly enhanced immune cell infiltration in solid tumors especially in combinatory with PD-1 blockade. We identified aberrant-RNA sensing signaling proteins (RIG-I/MAVS and PKR) in mediating the expression of IFN genes, as depletion of each of them blunted the elevation of anti-viral/IFN signaling in Xrn1 silenced cells. Analysis of pan-cancer CRISPR screening data indicated that IFN signaling triggered by Xrn1 silencing is a common phenomenon, suggesting that the effect of Xrn1 silencing may be extend to multiple types of cancers.

ORGANISM(S): Mus musculus

PROVIDER: GSE202587 | GEO | 2023/02/21

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

XRN1 knockdown stimulate innate immune reponse in murine melanoma cells

Project description:Despite the remarkable achievement of immune checkpoint blockade (ICB) therapy, the response rate is relatively low and only a subset of patients can benefit from the treatment. We hypothesize that targeting RNA decay machinery may lead to accumulation of aberrantRNA, triggering interferon (IFN) signaling and sensitizing tumor cells to immunotherapy. With this in mind, we identified an RNA exoribonuclease, XRN1 as a potential target. Silencing of XRN1 suppressed tumor growth in syngeneic immunocompetent mice and potentiated immunotherapy, while silencing of XRN1 alone did not affect tumor growth in immune deficient mice. Mechanistically, XRN1 depletion activated interferon signaling and viral defense pathway; both pathways play determinant roles in regulating immune evasion. We identified aberrant-RNA sensing signaling proteins (RIG-I/MAVS and PKR) in mediating the expression of IFN genes, as depletion of each of them blunted the elevation of anti-viral/IFN signaling in Xrn1 silenced cells. Analysis of pan-cancer CRISPR screening data indicated that IFN signaling triggered by Xrn1 silencing is a common phenomenon, suggesting that the effect of Xrn1 silencing may be extend to multiple types of cancers.

2023-02-21 | GSE199744 | GEO

Clinical and molecular features of acquired resistance to immunotherapy [RNA-seq]

Project description:Although immunotherapy with PD-(L)1 blockade is routine for lung cancer, little is known about acquired resistance. Among 1,201 patients with non-small cell lung cancer (NSCLC) treated with PD-(L)1 blockade, acquired resistance is common, occurring in >60% of initial responders. Acquired resistance shows differential expression of inflammation and interferon (IFN) signaling. Relapsed tumors can be separated by upregulated or stable expression of IFNγ response genes. Upregulation of IFNγ response genes is associated with putative routes of resistance characterized by signatures of persistent IFN signaling, immune dysfunction, and mutations in antigen presentation genes which can be recapitulated in multiple murine models of acquired resistance to PD-(L)1 blockade after in vitro IFNγ treatment. Acquired resistance to PD-(L)1 blockade in NSCLC is associated with an ongoing, but altered IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance informs therapeutic strategies to effectively reprogram and reverse acquired resistance.

2024-01-11 | GSE249000 | GEO

Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer

2024-01-11 | GSE248249 | GEO

Clinical and molecular features of acquired resistance to immunotherapy [ATAC-seq]

2024-01-11 | GSE249001 | GEO

Tumor cell intrinsic type I interferon signaling dictates CD47-SIRPα blockade immunotherapy via metabolic reprograming [dataset 2]

Project description:Type I interferons (IFN-Is) have been well recognized for their roles in immune cells in tumor immunotherapy. However, their direct effects on tumor cells are less understood. Oxidative phosphorylation (OXPHOS) is typically latent in tumor cells. However, whether OXPHOS can be targeted for immunotherapy remains unclear. Here, we found that tumor cell responsiveness to IFN-Is is essential for CD47-SIRPα blockade immunotherapy. Interestingly, IFN-Is directly reprogram tumor cell metabolism by activating OXPHOS for ATP production via ISG15. ATP extracellular release is also enhanced by IFN-Is via autophagy. Tumor cells with a genetic deficiency in OXPHOS or autophagy were resistant to CD47-SIRPα blockade. ATP released upon CD47-SIRPα blockade primes the anti-tumor T cell response via ATP-P2X7 receptor-mediated dendritic cell activation. Further combination with inhibitors of ATP-degrading ectoenzymes, CD39 and CD73, showed synergistic anti-tumor effects. Together, these data reveal the unrecognized mechanisms of IFN-Is on tumor cell metabolic reprograming in tumor immunotherapy and provide novel strategies harnessing this pathway for enhanced efficacy of CD47-SIRPα blockade.

2024-06-04 | GSE235112 | GEO

Chemohormonal Therapy Remodels Prostate Cancer Immune Microenvironment and Enhances Checkpoint Inhibitor-based immunotherapy

Project description:Checkpoint blockade immunotherapy is a promising strategy in cancer treatment, depending on a favorable preexisting tumor immune microenvironment. However, prostate cancer is usually considered as an immune “cold” tumor with the poor immunogenic response and low density of tumor-infiltrating immune cells. This research uses samples from prostate cancer patients showing that docetaxel-based chemohormonal therapy reprograms the immune microenvironment and increases tumor-infiltrating T cells. Mechanistically, docetaxel treatment activates the cGAS/STING pathway and induces the type I interferon signaling, which may boost T cell-mediated immune response. In a murine prostate cancer model, chemohormonal therapy sensitizes tumor-bearing mice to PD1-blockade therapy. These findings demonstrate that docetaxel-based chemohormonal therapy activates prostate cancer immunogenicity and acts cooperatively with anti-PD-1 checkpoint blockade, providing a combination immunotherapy strategy that would lead to better therapeutic benefit for prostate cancer.

2022-08-01 | GSE193898 | GEO

Reversing Epigenetic Gene Silencing to Overcome Immune Evasion in CNS Malignancies

Project description:Glioblastoma is an aggressive brain malignancy with a dismal prognosis. With emerging evidence that disproves the immune privileged environment in the brain, there is much interest in examining various immunotherapy strategies to treat these incurable cancers. Unfortunately, to date, clinical studies investigating immunotherapy regimens have not provided much evidence of efficacy, leading to questions about the suitability of immunotherapy strategies for these tumors. Inadequate inherent populations of lymphocytes in tumor (TILs) and limited trafficking of systemic circulating T cells into the central nervous system (CNS) likely contribute to the poor response to immunotherapy treatment for primary CNS cancers. This paucity of TILs is in concert with the finding of epigenetic silencing of genes that promote immune cell movement (chemotaxis) to the tumor. In this study we evaluated the ability of GSK126, a blood-brain barrier permeable small molecule inhibitor of EZH2, to reverse the epigenetic silencing of chemokines like CXCL9 and CXCL10. When combined with anti-PD-1 treatment, these IFN driven chemokines promote T cell infiltration, resulting in decreased tumor growth and enhanced survival in immunocompetent murine sub-cutaneous and intracranial tumor syngeneic models of GBM. Examination of the tumor micro-environment revealed that the decrease in tumor growth in the mice treated with the drug combination was accompanied by increased tumor CD8 T cell infiltration along with higher IFN expression. Additionally, a significant increase in CXCR3+ T cells in the draining lymph nodes was also found. Taken together, our data suggests that in glioblastoma, epigenetic modulation using GSK126 could improve current immunotherapy strategies by reversing the epigenetic changes that enable immune cell evasion leading to enhanced immune cell trafficking to the tumor.

2021-06-11 | ST001838 | MetabolomicsWorkbench

Ablation of Histone Demethylase KDM5B in Melanoma Augments Anti-Tumor Immunity through Upregulation of Retroelements [RNA-Seq YUMMER1.7-Kdm5b KO]

Project description:Purpose: Advanced melanoma patients have poor prognosis. Although immune checkpoint blockade has revolutionized treatment for melanoma patients, majority of patients do not respond. The goal of this research is to evaluate whether epigenetic therapy targeting KDM5B could overcome resistance to immunotherapy. Methods:RNA-Seq analysis of KDM5B KO mouse melanoma cell lines compared to control cells to evaluate whether KDM5B depletion induces activation of retroelements, which subsequently activates type I interferon responses. Mouse studies were conducted to evaluate whether anti-tumor immunity induced by KDM5B loss could overcome immunotherapy resistance. Results: We identified that KDM5B depletion derepress retroelement expression, which subsequently activates type I interferon response and enhances anti-tumor immunity. Loss of KDM5B could overcome resistance to anti-PD-1 immunotherapy. Conclusions: Our work characterized ablation of histone demethylase KDM5B in melanoma augments anti-tumor immunity through Upregulation of retroelements.

2021-07-25 | GSE161064 | GEO

Ablation of Histone Demethylase KDM5B in Melanoma Augments Anti-Tumor Immunity through Upregulation of Retroelements [RNA-Seq 1445-Kdm5b KO]

2021-07-25 | GSE161063 | GEO

Ubiquitin-activating enzyme mediates immune escape via suppressing interferon signaling

Project description:How cancer cells escape immune surveillance and resist immunotherapies remain to be elucidated. By screening candidate genes frequently amplified in cancer, we identified expression of ubiquitin-activating enzyme (UBA1) as being the most negatively correlated with signatures related to effector CD8+T cells. High expression of UBA1was strongly predictive of resistance to immune checkpoint blockade (ICB) and poor survival in ICB cohorts. In immunocompetent syngeneic models, but not in immunodeficient models, we found that overexpression ofUba1in cancer cells promoted tumor growth and reduced functional, intratumoral CD8+T cells. Conversely, depletion ofUba1impaired tumor progression, accompanied with increase of functional, intratumoral CD8+T cells. CD8+T cell depletion rescued tumor growth impairment mediated byUba1depletion. Additionally, a selective, small molecule inhibitor of UBA1, TAK-243, delayed tumor growth and augmented ICB in various syngeneic models, in a manner dependent on CD8+T cells. Intratumoral administration of TAK-243 and tumor rechallenge experiments revealed that TAK-243 treatment exhibited a remarkable abscopal effect and provided prolonged protection against cancer, accompanied with elevation of memory CD8+ T cells. Mechanistically, depletion or inactivation of UBA1 stabilized the short-lived interferon (IFN) pathway component, JAK1, upregulated both type-I and -II IFN signaling pathways, and resulted in elevation of key immune modulators, including CXCL9, CXCL10, and MHC-I. Taken together, our data supports that UBA1 mediates cancer immune escape via suppressing interferon signaling and suggests that targeting UBA1 may activate systemic cancer immunity.

2024-10-06 | GSE253880 | GEO

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