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High throughput characterization of human glioblastoma multiforme cell response to Type 1 interferons

ABSTRACT: Oncolytic virus therapy is a promising direction for cancer treatment. Numerous oncolytic viruses are under development or examined in clinical trials, there are examples of FDA approved virus vaccines. Although evident progress exists, oncolytic viruses still suffer low efficiency and the mechanisms of their action remain poorly understood. Defects in antiviral mechanisms that include type I interferon (IFN) signaling, contribute to sensitivity of malignant cells to oncolytic viruses, however, this sensitivity significantly differs for different malignant cells. In this project, we present a collection of representative transcriptomics and proteomics data for primary glioblastoma multiforme (GBM) cell cultures with established sensitivity to type I IFNs and the comprehensive characterization of GBM responses at both protein and RNA levels. Analysis demonstrated that GBM cells can respond to treatment by extreme upregulation of IFN-induced genes that is very similar to classic response in normal human cells. GBM cultures can significantly differ from each other by a value of transcriptome and proteome changes that are well correlated with sensitivity tests. In our data, upregulation of IFIT1/2/3, OAS1/2/3/L, MX1/2 among the others, was a reproducible marker for the developed resistance of GBM cells to vesicular stomatitis virus (VSV).

ORGANISM(S): Homo sapiens

PROVIDER: GSE163949 | GEO | 2021/12/29

REPOSITORIES: GEO

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Comparative proteomics for identification of type I interferon response in primary human glioblastoma multiforme cells

Project description:Oncolytic virus therapy is a promising direction for cancer treatment. Numerous oncolytic virus strains are under development or examined in clinical trials, there are examples of FDA approved virus vaccines. Although evident progress exists, oncolytic viruses still suffer low efficiency and the mechanisms of their action remain poorly understood. Defects in antiviral mechanisms that include type I interferon (IFN) signaling, contribute to sensitivity of malignant cells to oncolytic viruses, however, this sensitivity significantly differs for different malignant cells. In this project, we present a collection of representative proteomics data for eight primary glioblastoma multiforme (GBM) cell cultures and one culture of normal astrocytes with established sensitivity to type I IFNs that comprehensively characterize the GBM cell responses to type I IFNs. Project consists of three parts: (1) label-free proteomics of primary GBM cultures on Orbitrap Fusion Lumos; (2) label-free proteomics of primary GBM and normal astrocytes on Orbitrap QExactive HF; (3) label-based proteomics of wild type, IFIT3-deficient and PLSCR1-deficient DBTRG-05MG cells (ATCC) on Q-Exactive Plus.

2022-02-03 | PXD022836 | Pride

Comparative proteomics for identification of type I interferon response in primary human glioblastoma multiforme cells

Project description:Oncolytic virus therapy is a promising direction for cancer treatment. Numerous oncolytic virus strains are under development or examined in clinical trials, there are examples of FDA approved virus vaccines. Although evident progress exists, oncolytic viruses still suffer low efficiency and the mechanisms of their action remain poorly understood. Defects in antiviral mechanisms that include type I interferon (IFN) signaling, contribute to sensitivity of malignant cells to oncolytic viruses, however, this sensitivity significantly differs for different malignant cells. In this project, we present a collection of representative proteomics data for eight primary glioblastoma multiforme (GBM) cell cultures and one culture of normal astrocytes with established sensitivity to type I IFNs that comprehensively characterize the GBM cell responses to type I IFNs. Project consists of three parts: (1) label-free proteomics of primary GBM cultures on Orbitrap Fusion Lumos (a separate dataset); (2) label-free proteomics of primary GBM and normal astrocytes on Orbitrap QExactive HF; (3) label-based proteomics of wild type, IFIT3-deficient and PLSCR1-deficient DBTRG-05MG cells (ATCC) on Q-Exactive Plus.

2022-02-03 | PXD022906 | Pride

Comparative proteomics for identifying specific alterations within interferon response pathways in human glioblastoma multiforme and osteosarcoma cells

Project description:An acquisition of increased sensitivity of cancer cells to viruses is a common outcome of malignant progression that justifies the development of oncolytic viruses as anticancer therapeutics. Studying molecular changes that underlie the sensitivity to viruses would help to identify cases where oncolytic virus therapy would be most effective. We quantified changes in protein abundances in glioblastoma multiforme (GBM) and osteosarcoma cell lines that differ in the ability to induce resistance to vesicular stomatitis virus (VSV) infection in response to type I interferon (IFN) treatment. In IFN-treated samples we observed an up-regulation of protein products of some IFN-regulated genes (IRGs). In total, the proteome analysis revealed up to 20% more proteins encoded by IRGs in the glioblastoma cell line, which develops resistance to VSV infection after pre-treatment with IFN. In both cell lines protein-protein interaction and signaling pathway analyses have revealed a significant stimulation of processes related to type I IFN signaling and defense responses to viruses. The study has shown that the up-regulation of IRG proteins induced by the IFNα treatment of GBM cells can be detected at the proteome level. Similar analyses could be applied for revealing functional alterations within the antiviral mechanisms in glioblastoma samples, accompanying by acquisition of sensitivity to oncolytic viruses.

2022-06-09 | PXD022868 | Pride

Model based Rational Design of an Oncolytic Virus with Improved Therapeutic Potential

Project description:Oncolytic viruses are complex biological agents that interact at multiple levels with both tumor and normal tissues. Anti-viral pathways induced by interferon are known to play a critical role in determining tumor cell sensitivity and normal cell resistance to infection with oncolytic viruses. Here we pursue a synthetic biology approach to identify methods that enhance anti-tumor activity of oncolytic viruses through suppression of IFN signaling. Based on the mathematical analysis of multiple strategies, we hypothesize that a positive feedback loop, established by virus-mediated expression of a soluble interferon-binding decoy receptor, increases tumor cytotoxicity without compromising normal cells. Oncolytic rhabodviruses engineered to express a secreted interferon antagonist have improved oncolytic potential in cellular cancer models, and display improved therapeutic potential in tumor-bearing mice. Our results demonstrate the potential of this methodology in evaluating potential caveats of viral immune evasion strategies and improving the design of oncolytic viruses. The following series of microarray experiments was utilized to assess the impact of cloning an IFN decoy receptor isolated from vaccinia virus termed B19R on the transcriptional response against an IFN sensitive maraba virus strain termed MG1. RNA extraction was performed 24h post infection in 786-0 cells. Duplicate samples were pooled, and hybridized on Affymetrix human gene 1.0 ST arrays according to manufacturer instructions. Data analysis was performed using AltAnalyze. Briefly, probeset filtering implemented a DABG threshold of 70 & pV<0.05 and utilized exclusively constitutively expressed exons to assess levels of gene expression.

2013-06-01 | E-MTAB-1636 | biostudies-arrayexpress

Transcription profiling of human MPNST cancer cells infected with G207 an oncolytic HSV

Project description:We used microarrays to identify genes regulated during oncolytic HSV infection. Oncolytic herpes simplex viruses (oHSV) are promising anticancer therapeutics. We sought to identify alterations in gene expression during oHSV infection of human cancer cells. Human malignant peripheral nerve sheath tumor (MPNST) cells were infected with G207, an ICP34.5-deleted oHSV previously evaluated in clinical trials. G207-infected cells demonstrated massive degradation of cellular mRNAs, while a subset were upregulated. A gene signature of 21 oHSV-induced genes contained 7 genes known to be HSV-induced. Go ontology classification revealed that a majority of upregulated genes are involved in Jak/STAT signaling, transcriptional regulation, nucleic acid metabolism, protein synthesis and apoptosis. Ingenuity-defined functional networks highlighted nodes for AP-1 subunits and interferon signaling via STAT1, SOCS1, SOCS3 and RANTES. Upregulation of SOCS1 correlated with sensitivity of MPNST lines to G207 and depletion of SOCS1 reduced virus replication >1-log. The transcriptome of oHSV-induced genes may predict oncolytic efficacy and provides rationale for next generation oncolytics. Experiment Overall Design: 5 human MPNST cancer cell lines were infected with G207 or mock infected for 6 hours followed by RNA extraction and hybridization on Affymetrix microarrays.

2008-06-16 | E-GEOD-8717 | biostudies-arrayexpress

Correlative analysis from a phase I clinical trial of intrapleural administration of oncolytic vaccinia virus (Olvi-vec) in patients with malignant pleural mesothelioma

Project description:Regional delivery of oncolytic viruses has been shown to promote immune responses. Malignant pleural effusions comprise an immunosuppressive microenvironment, and the ability of oncolytic viruses to generate immune responses following regional delivery in patients with malignant pleural effusions is unknown. We conducted a phase I clinical trial that studied the intrapleural administration of oncolytic vaccinia virus to establish the safety and feasibility in patients with malignant pleural effusion due to malignant pleural mesothelioma or metastatic disease. In patients with malignant pleural mesothelioma, by correlative analysis of pre- and post-treatment tumor biopsies, we provide insight into tumor-specific viral uptake and associated immune responses.

2023-01-27 | GSE223395 | GEO

Expression data from Human MPNST cancer cells infected with G207 and oncolytic HSV

2007-08-08 | GSE8717 | GEO

Single-cell RNA sequencing reveals a strong connection between Gadd45g upregulation and oncolytic HSV infection in tumor tissue

Project description:The oncolytic effect of virotherapy derives from the intrinsic capability of the applied virus in selectively infecting and killing tumor cells. Although oncolytic viruses of various constructions have been shown to efficiently infect and kill tumor cells in vitro, the efficiency of these viruses to exert the same effect on tumor cells within tumor tissues in vivo has not been extensively investigated. Here we report our studies using single-cell RNA sequencing to comprehensively analyze the gene expression profile of tumor tissues following herpes simplex virus 2-based oncolytic virotherapy. Our data revealed the extent and cell types within the tumor microenvironment that could be infected by the virus. Moreover, we observed changes in the expression of cellular genes, including antiviral genes, in response to viral infection. One notable gene found to be upregulated significantly in oncolytic virus-infected tumor cells was Gadd45g, which is desirable for optimal virus replication. These results not only help reveal the precise infection status of the oncolytic virus in vivo, but also provide insight that may lead to the development of new strategies to further enhance the therapeutic efficacy of oncolytic virotherapy.

2021-10-31 | GSE186753 | GEO

More than a ligand: PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I interferon pathway

Project description:Targeting the PD-1/PD-L1 axis has transformed the field of immune-oncology. While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell‑intrinsic functions in immune and cancer cells. In line with these studies, here we show that PD-L1 potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cells resulted in enhanced infection with oncolytic viruses in cancer cells in vitro and in vivo. PD-L1 expression marks tumor explants from cancer patients that are best infected by oncolytic viruses. Agonistic antibodies targeting PD-L1 further reduced type I IFN responses and enhanced oncolytic virus infection. Mechanistically, PD-L1 suppressed type I interferon by promoting Warburg metabolism, characterized by enhanced glucose uptake and glycolysis rate. Lactate generated from glycolysis was the key metabolite responsible for inhibiting type I interferon responses and enhancing oncolytic virus infection in PD‑L1‑expressing cells. In addition to adding mechanistic insight into PD-L1 intrinsic function and showing that PD-L1 has a broader impact on immunity and cancer biology besides acting as a ligand for PD-1, our results will also help guide the numerous efforts currently ongoing to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials.

2023-06-28 | GSE210884 | GEO

Histone deacetylase inhibitors (HDACi) enhance oncolytic herpes simplex virus in malignant meningioma.

Project description:The goal of the study was to determine whether low dose HDACi sensitizes human malignant meningioma cells to the cytotoxic capacity of oncolytic herpes simplex virus G47delta. RNA sequencing was used to examine transcriptomic changes mediated by HDACi preexposure before oncolytic virus infection.

2022-08-02 | GSE210178 | GEO

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