Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Digital Spatial Profiling of immuno-oncology proteins in mouse hepatocellular carcinoma xenograft treated with THIO-based combination immune therapie

ABSTRACT: THIO (6-thio-dG) is a nucleoside analog that induces telomeric DNA damage and triggers activation of anti-tumor immunity in several cancer types such as lung and colorectal cancers. To evaluate its effect in hepatocellular carcinoma (HCC), THIO in combination with the current standard care first-line therapy for advanced HCC, anti-PD-L1 and anti-analyze, was tested in immunocompetent mice subcutaneously implanted with syngeneic HCC cell line (Hep55.1c). Formalin-fixed paraffin-embedded (FFPE) tumor tissues were collected after the treatment, and therapeutic modulations of the tumor immune landscape were assessed with Digital Spatial Profiling of 38 immuno-oncology-related proteins in region of interest (ROI) and intra-ROI segments enriched for T cells, other leukocytes, and HCC/stromal cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE219108 | GEO | 2023/06/07

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Gene Expression Analysis of Melanoma Cells Treated with 6-Thio-dG In Vitro

Project description:Telomerase promoter mutations are highly prevalent in human tumors including melanoma. Telomere transcriptional signatures are enriched in a subset of therapy-naïve melanomas associated with worse overall survival, in BRAF-mutant intrinsically resistant melanoma cells that evade MAPK inhibitors (MAPKi), as well as in a subset of post-treatment tumor biopsies derived from patients who have disease progression on MAPKi or the immune checkpoint inhibitors, anti-CTLA-4 or anti-PD1. We demonstrate the efficacy of a telomerase-directed nucleoside, 6-thio-2'-deoxyguanosine (6-thio-dG) that results in telomere dysfunction and cell death in various models of therapy-resistant cells. Furthermore, 6-thio-dG significantly inhibits tumor growth of primary tumor biopsy cultures derived from patients who had disease progression on multiple therapies including anti-CTLA-4 or anti-PD1.

2017-06-02 | GSE99552 | GEO

Exploring the Effect and Mechanisms of Telomerase Inhibition as A Novel Therapeutic Strategy for Glioma

Project description:The obejctive of this study is to establish the therapeutic role of 6-thio-dG for gliomas in vitro and in vivo and to elucidate the anti-tumor mechanisms of 6-thio-dG in glioma cells. And the ultimate goal of this proposal is to demonstrate the potential of 6-thio-dG as a novel strategy for primary and recurrent glioma.

2021-09-13 | GSE160619 | GEO

Exploring the Effect and Mechanisms of Telomerase Inhibition as A Novel Therapeutic Strategy for Glioma [2224, DBTGR-05MG, A172]

2021-09-13 | GSE180874 | GEO

Telomerase-mediated Strategy for Overcoming Non-Small Cell Lung Cancer Targeted Therapy and Multi-drug Chemotherapy Resistance

Project description:Standard and targeted therapies almost universally fail due to tumor heterogeneity/plasticity leading to intrinsic or acquired drug resistance. We used the telomerase substrate precursor 6-thio-2’-deoxyguanosine (6-thio-dG) to target telomerase-expressing targeted therapy and platin-doublet chemotherapy resistant cells. We observed that erlotinib, paclitaxel/carboplatin and gemcitabine/cisplatin resistant cells are sensitive to 6-thio-dG in xenograft, syngeneic immunocompetent and genetically engineered mouse models. We also show sensitivity to 6-thio-dG on a large panel of non-small cell lung cancer cell lines (73 of 77). The 4 resistant NSCLC lines clustered together, providing a molecular signature for patients that may not respond to 6-thio-dG. We find SLC43A3 as a top candidate in this molecular signature. Thus, 6-thio-dG may prolong disease control of therapy-resistant lung cancer patients.

2018-01-30 | GSE109821 | GEO

AVA-ADR-001- a small molecular inhibitor of ADAR1 (Immuno-oncology target)

Project description:To inhibitors for ADAR1 and a strong rationale for the development of ADAR1 p150 inhibitors for cancer immunotherapy Here, we describe AVA-ADR-001, a potential first-in-class small molecule inhibitor of ADAR1 p150 targeting the Z alpha domain. AVA-ADR-001 binds specifically to the Z alpha domain of ADAR1 p150 as confirmed by fluorescence spectroscopy and showed significant interferon induction in THP1 macrophages, which have high ADAR1 p150 expression compared with monocytes. Proteomics and transcriptomics analysis revealed significant upregulation of interferon signaling upon treatment with AVA-ADR -001. Interestingly, activation of interferon signaling resulted in AVA-ADR-001 induced cell killing in ADAR1-independent cell lines. In addition, treatment with AVA-ADR -001 resulted in significant activation of PKR, which may explain the decreased cell proliferation. Finally, AVA-ADR-001 showed superior anti-tumor efficacy compared to anti-PD1 in an in vivo tumor efficacy study and has a moderately synergistic effect when combined. Overall, this study reveals that ADAR1 p150 inhibition by AVA-ADR-001 exerts a multipronged impact on anti-tumor efficacy mediated by immune cells, accumulation of interferons and activation of PKR, resulting in protein translation inhibition and cell proliferation arrest.

2023-04-17 | GSE229503 | GEO

Analysis of queuosine and 2-thio tRNA modifications by high throughput sequencing

Project description:Queuosine (Q) is a conserved tRNA modification at the wobble anticodon position of tRNAs that read the codons of amino acids Tyr, His, Asn, and Asp. Q-modification in tRNA plays important roles in the regulation of translation efficiency and fidelity. Queuosine tRNA modification is synthesized de novo in bacteria, whereas the substrate for Q-modification in tRNA in mammals is queuine, the catabolic product of the Q-base of gut bacteria. This gut microbiome dependent tRNA modification may play pivotal roles in translational regulation in different cellular contexts, but extensive studies of Q-modification biology are hindered by the lack of high throughput sequencing methods for its detection and quantitation. Here, we describe a periodate-treatment method of biological RNA samples that enables single base resolution profiling of Q-modification in tRNAs by Nextgen sequencing. Periodate oxidizes the Q-base, which results in specific deletion signatures in the RNA-seq data. Unexpectedly, we found that periodate-treatment also enables the detection of several 2-thio-modifications including τm5s2U, mcm5s2U, cmnm5s2U, and s2C by sequencing in human and E. coli tRNA. We term this method Periodate-dependent analysis of queuosine and thio modification sequencing (PAQS-seq). We assess Q- and 2-thio-modifications at the tRNA isodecoder level, and 2-thio modification changes in stress response. PAQS-seq should be widely applicable in the biological studies of Q- and 2-thio-modifications in mammalian and microbial tRNAs.

2022-06-22 | GSE196016 | GEO

Spleen vs 2-Methyl-thio-ATP Treated B cell

Project description:total RNA from mouse (male c57BL/6) spleen labeled with Cy3 vs total RNA from mouse (male c57BL/6) B cells treated with 2-Methyl-thio-ATP labeled with Cy5- time course with repeats Keywords: ordered

2003-04-14 | GSE370 | GEO

Spatial immuno-oncology protein abundance profiles in hepatocellular carcinoma tissues from patients treated with bavituximab and pembrolizumab

Project description:Immune checkpoint inhibitors (ICIs) targeting PD-1/L1 have modest efficacy in hepatocellular carcinoma (HCC) as single agents, but combination regimens have demonstrated increased clinical benefit at the expense of treatment toxicities. Exposed phosphatidylserine suppresses the innate immune response in the tumor microenvironment (TME). Targeting phosphatidylserine does not induce tumor responses in the clinical setting when used as monotherapy or in combination with cytotoxic and targeted therapies, but may induce pro-inflammatory and –immune stimulating effects that enhance ICI activity. This hypothesis was tested in a single-arm phase 2 trial evaluating bavituximab, a phosphatidylserine targeting antibody, plus pembrolizumab in patients with unresectable HCC who had not received prior systemic treatments (ClinicalTrials.gov ID: NCT03519997). The primary end point was investigator-assessed objective response rate (ORR) among evaluable patients, and secondary end points included progression-free survival (PFS) and the incidence of adverse events. Among 28 evaluable patients, the ORR was 32.1%, including 2 complete responses, and a disease control rate of 64.3%. Median PFS was 6.3 months (95% CI, 1.3-11.3 months). Treatment related adverse events of any grade occurred in 45.7% of patients with grade 3 or 4 adverse events occurring in 14.3% of patients. Exploratory analyses of baseline tumor specimens showed that a depletion of B cells, and the expression of smooth muscle actin and immune checkpoints in stroma was associated with tumor response. An RNA-based TME assay which distinguishes immune-rich of inflammatory tumors was also shown to be predictive of ORR. These results suggest that targeting phosphatidylserine may lead to synergistic effects with ICIs without increasing toxicity rates, and future studies on this therapeutic strategy may be guided by biomarkers characterizing the TME.

2024-02-08 | GSE242154 | GEO