Intravenous injection of oncolytic virus M1 awakes antitumor T cells and overcomes resistance to checkpoint blockade
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE152451 | GEO | 2020/12/21
REPOSITORIES: GEO
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Project description:Gene set enhancement analysis (GSEA) revealed that M1 treatment upregulates glycolysis and hypoxia pathway in hallmark gene sets. GSEA revealed that Lonidamine strongly inhibited the IFN-α and IFN-β response pathways after M1 virus infection. GSEA showed that gene sets in unfolded protein response, response to endoplasmic reticulum stress, intrinsic apoptotic signaling pathway were significantly upregulated by Lonidamine plus M1 treatment.
2020-11-16 | GSE152876 | GEO
Project description:Immunogenic cell death (ICD) in cancer represents a functionally unique therapeutic response that can induce tumor-targeting immune responses. ICD is characterized by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which confer adjuvanticity to dying cancer cells. The spatiotemporally defined emission of DAMPs during ICD has been well described; whereas the epigenetic mechanisms that regulate ICD hallmarks have not yet been deeply elucidated. Here, we aimed to examine the involvement of miRNAs and their putative targets taking advantage from well-established in vitro models of ICD. To this end, B cell lymphoma (Mino) and breast cancer (MDA-MB-231) cell lines were exposed to two different ICD inducers: the combination of retinoic acid (RA) and interferon-alpha (IFN-a) and doxorubicin, and to non ICD inducers like gamma irradiation. Then, miRNA and mRNA profiles were studied by next generation sequencing. Co-expression analysis identified 16 miRNAs differentially modulated in cells subjected to ICD. Integrated miRNA-mRNA functional analysis revealed candidate miRNAs, mRNAs, and modulated pathways associated with Immune System Process (GO Term). In this sense, ICD induced a distinctive transcriptional signature hallmarked by regulation of antigen presentation, a crucial step for a proper immune system antitumor response activation. Interestingly, the major histocompatibility complex class I (MHC-I) pathway was upregulated whereas class II (MHC-II) was downregulated. Analysis of MHC-II associated transcripts and HLA-DR surface expression validated the inhibition of this pathway by ICD on lymphoma cells. miR-4284 and miR-212-3p were the strongest miRNAs upregulated by ICD associated with this event. It is well known that MHC-II expression on tumor cells facilitates the recruitment of CD4+ T cells. However, the interaction between tumor MHC-II and the inhibitory co-receptor LAG-3 on tumor-associated lymphocytes could provide an immunosuppressive signal that directly represses effector cytotoxic activity. In this context, MHC-II downregulation by ICD could enhance antitumor immunity. Overall, we found that the miRNA profile was significantly altered during ICD. Several miRNAs are predicted to be involved in the regulation of Class I and II MHC pathway, whose implication in ICD was demonstrated herein for the first time, which could eventually modulate tumor recognition and attack by the immune system.
2022-08-08 | E-MTAB-11799 | biostudies-arrayexpress
Project description:Tumor microenvironment (TME)-induced nanocatalytic therapy is a promising strategy for cancer treatment, but the low catalytic efficiency limits its therapeutic efficacy. Single-atom catalysts (SACs) are a new type of nanozyme with incredible catalytic efficiency. Here we construct a single-atom manganese (Mn)-N/C nanozyme. Mn-N/C catalyzes the conversion of cellular H2O2 to ∙OH through a Fenton-like reaction and enables the sufficient generation of reactive oxygen species (ROS), which induces immunogenic cell death (ICD) of tumor cells and significantly promotes CD8+T anti-tumor immunity. Moreover, RNA sequencing reveals that Mn-N/C treatment activates type I interferon (IFN) signaling which is critical for Mn-N/C-mediated anti-tumor immune response. Mechanistically, Mn-N/C-triggered releasing of cytosolic DNA from ICD tumor cells activates cGAS-STING pathway, consequently stimulating type I IFN induction. We propose a new promising single-atom nanozyme with extraordinary catalytic activity, which enhances anti-tumor immune response and exhibits synergistic therapeutic effects when combined with anti-PD-L1 blockade.
2024-04-24 | GSE249852 | GEO
Project description:Macrophages acquire distinct phenotypes during tissue stress and inflammatory responses. Classically, macrophages are categorized into two different subsets named inflammatory M1 and anti-inflammatory M2 macrophages. We herein identified a unique pathogenic macrophage subpopulation, named M17, driven by IL-23 with a distinct gene expression profile including cytokines and membrane molecules. In contrast to M1 and M2-polarized macrophages, M17 macrophages express high levels of CXCR5 on the cell surface and produce large amounts of IL-17A, IL-22 and IFN-γ. IL-23 induces IL-17A expression in macrophages through the signal transducer and activator of transcription 3 (STAT3)-retinoid related orphan receptor-γ T (RORγT) pathway, while induces IFN-γ through T-bet. Importantly, IL-23-induced M17 macrophage polarization promotes the pathogenesis of psoriasis in vivo. The characteristics and significances of M17 macrophage subpopulation in the physiological status and pathogenesis caused by infections, tumors and graft rejection needs to be explored.
2018-03-12 | GSE102274 | GEO
Project description:Macrophages acquire a pro-inflammatory M1 phenotype in response to microbial products or pro-inflammatory cytokines through incompletely understood molecular mechanisms. We recently described the induction of APOBEC3A-mediated cellular site-specific cytosine-to-uracil (C>U) RNA editing during M1 macrophage polarization. However, the functional significance of this RNA editing is unknown. Here, we find that cellular RNA editing by APOBEC3A can also be induced by influenza or Maraba virus infections in normal macrophages, and by interferons in tumor-associated macrophages. Gene knockdown and RNA Seq analyses show that APOBEC3A induces C>U RNA editing (range 7%-88%) of 209 exonic or UTR sites in 203 genes during M1 polarization of monocyte-derived macrophages. The highest level of deleterious protein-recoding C>U RNA editing is observed in THOC5, which encodes a key nuclear protein implicated in the export of mRNAs during M-CSF driven macrophage differentiation. Knockdown of APOBEC3A in M1 macrophages reduces pro-inflammatory IL6, IL23A, and IL12B gene expression, CD80 and CD86 surface protein expression, and TNF-α, IL-1β and IL-6 cytokine secretion, and increases glycolysis and glycolytic capacity. These results demonstrate that APOBEC3A cytidine deaminase plays an important role in transcriptomic and functional polarization of pro-inflammatory M1 macrophages.
2020-03-13 | GSE146867 | GEO
Project description:Macrophages are known to be polarized into inflammatory (M1) and immunoregulatory (M2) cells when they are stimulated by agonists such as IFN-gamma and IL-4, respectively. If circulating monocytes may be polarized in response to T cell signals is often misguidedly deduced from macrophage results. Here the transcriptional responses of human CD14+ monocytes to IFN-gamma and IL-4 were analyzed using whole genome microarrays. A principal component analysis and hierarchical clustering showed that monocyte and macrophage responses were distinct. Monocytes stimulated with IFN-gamma and IL-4 for 6 hours exhibited some features of macrophage polarization. Indeed, when 80 genes considered as M1 and M2 genes were analyzed, we found that M1 genes were modulated in response to IFN-gamma and that M2 genes were modulated in response to IL-4. The M1 polarization of monocytes was transient because only M2 genes were modulated when monocytes were stimulated with IFN-gamma and IL-4 for 18 hours. However, the activation of monocytes by IFN-gamma and IL-4 could not be reduced to M1/M2 polarization status. Indeed, monocytes exhibited early specific signatures composed of 46 and 39 up-regulated genes in response to IFN-gamma and IL-4, respectively, and a late signature common to both molecules that consisted of 57 up-regulated genes. Taken together, these results demonstrated the extreme plasticity of human monocytes and suggested the existence of a core transcriptional termination program. Using early and late signatures might be pertinent to investigate monocyte activation in inflammatory or infectious diseases. Monocytes were stimulated with IFN-gamma (20ng/mL) or IL-4 (20ng/mL) for 6 and 18 hours or culture for 6 and 18 hours without agonist (Unstimulated samples). Monocytes-derived-macrophages (MDM) stimulated with IFN-gamma and IL-4 for 18 hours were used as controls. Each microarray is derived from a single biological sample.
2013-03-15 | E-GEOD-36537 | biostudies-arrayexpress
Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to evaluate the gene expression of M1-polarized RAW264.7 cells compared with M0 RAW264.7 cells. Methods: RAW264.7 cells were polarized toward M1 using LPS and IFN-γ. M0 RAW264.7 cells were maintained in culture without LPS and IFN-γ. Total RNA of M1 and M0 RAW264.7 cells was extracted. RAW264.7 cells RNA profiles were generated by deep sequencing for two groups (M1 versus M0 RAW264.7 cells) with three samples each. Results: There were significant differences between M1 and M0 RAW264.7 cells. Conclusions: Polarization of RAW264.7 cells from M0 to M1 induces various changes at the transcription level.
2024-03-31 | GSE183077 | GEO
Project description:Virus infection is a kind of immune stimulation, except anti-viral factors, virus also induce tumor cells to secret cytokines which act on neighboring cells. Figuring out the exact cytokines upregulated by M1 virus is of great significance. We used microarry data to detail the expression of cytokines, chemokines and Inflammasomes regulated by oncolytic virus M1.
2016-12-27 | GSE92918 | GEO
Project description:Interferon (IFN)-alpha causes high rates of depression and fatigue, and is used to investigate the impact of innate immune cytokines on brain and behavior. However, little is known about transcriptional profiles of circulating immune cells during chronic IFN-alpha administration. Accordingly, genome-wide transcriptional profiling was performed on peripheral blood mononuclear cells from 21 patients with chronic hepatitis C virus either awaiting IFN-alpha therapy (n=10) or after 12 weeks of IFN-alpha treatment (n=11). Significance analysis of microarray data identified 252 up-regulated gene transcripts, the majority of which were related to IFN-alpha/antiviral or innate-immune/inflammatory signaling. Of these upregulated genes, 2'-5'-oligoadenylate synthetase 2 (OAS2) was the only gene that was differentially expressed in patients that developed IFN-alpha-induced depression/fatigue, and correlated with depression and fatigue scores at 12 weeks of IFN-alpha administration. Promoter-based bioinformatic and cellular origin analyses revealed IFN-alpha-induced increases in genes bearing transcription factor binding motifs (TFBMs) related to myeloid differentiation, IFN-alpha signaling, API and CREB/ATF family of transcription pathways, with changes derived primarily from monocytes and plasmacytoid dendritic cells. Patients with high depression/fatigue scores demonstrated up-regulation of genes bearing TFBMs for myeloid differentiation, IFN-alpha and AP1 signaling, and down regulation of TFBMs for CREB/ATF-related transcription factors. Cellular origin analyses indicated a shift toward genes derived from CD8+T and NK cells in subjects with high depression/fatigue scores. These results reveal an antiviral and inflammatory transcriptional profile after 12 weeks IFN-alpha, accompanied by increased OAS2 expression, decreased CREB/ATF transcriptional control, and a shift from monocyte-derived genes to those of cytotoxic lymphocytes in IFN-alpha-induced depression/fatigue. Total RNA was isolated from the peripheral blood mononuclear cells (PBMC) obtained at 12 weeks from HCV patients treated with IFN-alpha plus ribavirin (n=11) and untreated HCV patients awaiting IFN-alpha/ribavirin therapy (control subjects, n=10).
2012-01-01 | E-GEOD-31187 | biostudies-arrayexpress
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