Interaction between tumor cell TNFR2 and monocyte membrane-bound TNFα triggers tumorigenic inflammation in neuroblastoma
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PROVIDER: PRJNA906130 | ENA |
REPOSITORIES: ENA
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Project description:We found that NB expression of TNFR2 and monocyte mTNFα are required for monocyte activation and IL-6 production, while NB TNFR1 and monocyte sTNFα are required for NB NF-κB activation. Treatment of NB-monocyte co-cultures with clinical-grade etanercept completely abrogated release of IL-6, G-CSF, IL-1α, and IL-1β and eliminated monocyte-induced enhancement of NB cell proliferation in vitro. Furthermore, etanercept treatment inhibited tumor growth, ablated tumor angiogenesis, and suppressed oncogenic signaling in mice with subcutaneous NB/human monocyte xenografts. Finally, GSEA revealed significant enrichment for TNFα signaling in NB patients that relapsed.
2023-02-02 | GSE218915 | GEO
Project description:Natural Killer (NK) cells are predominant innate lymphocytes that provide the early response during infection. NK cells undergo metabolic switch to fuel augmented proliferation and activation following infection. TNFα is a well-known inammatory cytokine that enhances NK cell function, however, a mechanism for stimulation is not well established. Here, we demonstrated that upon infection/inammation, NK cells upregulate the expression of TNF receptor 2 (TNFR2), which is associated with increased proliferation, metabolic activity and effector function. Notably, IL-18 can induce TNFR2 on NK cells, augmenting their sensitivity towards TNFα. Mechanistically, TNFα-TNFR2 signaling induces CD25 (IL-2Rα) expression on NK cells predominantly by autocrine mode, leading to a metabolic switch towards aerobic glycolysis. Accordingly, genetic ablation of TNFR2 curtails the CD25 upregulation and TNFα-induced glycolysis, leading to impaired NK cell proliferation during MCMV infection in vivo. Collectively, our results delineate the crucial role of the TNFα-TNFR2 axis in NK cells for proliferation, glycolysis, and effector function via CD25 induction.
2023-09-26 | GSE235545 | GEO
Project description:Next Generation Sequencing Facilitates Quantitative Analysis of Wild Type, Tnfrsf1α-/- and Tnfrsf1β-/- (with or without TNFα treat) HPCs Transcriptomes.The mRNA profiles of Wild Type, Tnfrsf1α-/- and Tnfrsf1β-/- (with or without TNFα treat) HPCs were generated by deep sequencing, in triplicate, using Illumina GAIIx. The sequence reads that passed quality filters were analyzed at the transcript isoform level . qRT–PCR validation was performed using TaqMan and SYBR Green assays.We performed RNA-seq analysis to assess the global impacts of TNFR2 on HPCs' response to TNFα. Upon TNFα treatment, 519 genes were significantly upregulated in wild type HPCs . 39% of these genes (203 out of 519) were further upregulated in Tnfrsf1a-/- HPCs treated with TNFα. However, these 203 genes were dramatically downregulated in TNFα-treated Tnfrsf1b-/- HPCs relative to their expression in either TNFα-treated Tnfrsf1a-/- HPCs or wild type HPCs, indicating an inhibitory role for deletion of TNFR2 in the regulation of these genes.
2021-06-09 | GSE166627 | GEO
Project description:TNFα/TNFR2 axis mediates natural killer cell proliferation by enhancing their glycolytic plasticity
| PRJNA986437 | ENA
Project description:PURPOSE: The goal of this study was to determine the gene expression networks regulated by tumor necrosis factor receptor 2 (TNFR2, or Tnfrsf1b) and to evaluate their potential bearing on immune cell subsets and inflammatory bowel disease (IBD). METHODS: mRNA-seq was performed on isolated distal colons from TNFR2-knockout and wildtype mice. Differentially expressed transcripts were compared to human ulcerative colitis microarray datasets on Gene Expression Omnibus and to mouse immunological expression datasets at the Immunological Genome Project. RESULTS: We identified 252 mouse transcripts whose expressions were significantly altered by the loss of TNFR2. The majority of these transcripts (228 of 252, ~90%) were downregulated in TNFR2-/- colons. TNFR2-regulated genes were able to positively discriminate between ulcerative colitis patients and healthy individuals with ~80% accuracy. Many TNFR2-regulated genes were also highly expressed in CD8+ T cells. CONCLUSIONS: Downregulation of TNFR2 is associated with a gene expression profile that is prominent in IBD and supportive of the role of CD8+ T cells in IBD pathogenesis. MANUSCRIPT ABSTRACT: Increased tumor necrosis factor (TNF) production has been associated with inflammatory bowel disease (IBD), and anti-TNF therapy is a common therapeutic for this patient population. However, the role of TNF or its receptors (TNFR1 and TNFR2) in the immunopathogenesis of inflammatory bowel disease (IBD) remains unclear. Here we report that TNFR2 is protective in spontaneous (IL-10 knockout) and chemically (azoxymethane/dextran sodium sulfate)-induced mouse models of colitis and colitis-associated cancer. Mechanistically, TNFR2-deficiency in hematopoietic cells significantly increased incidence and severity of colitis and colitis-associated cancer characterized by a selective expansion of CD8+ T cells. We identified TNFR2-regulated genes in the colon that were specific for CD8+ T cells, interacted with multiple IBD risk genes, and are important regulators of CD8+ T cell biology. TNFR2 regulated CD8+ T-cell-specific genes that act as genetic susceptibility modifiers for IBD to mitigate the development of a pro-colitogenic milieu. Antibody-mediated depletion of CD8+ T cells prevented colonic inflammation and significantly reduced pathology in IL10-/-/TNFR2-/- deficient mice. Furthermore, adoptive transfer of TNFR2-/- naïve CD8+ T cells resulted in more severe disease than with wildtype naïve CD8+ T cells. Our findings provide insight into the disease modifier role of TNFR2 in the immunopathogenesis of IBD through the modulation of CD8+ T cell responses and support future investigation of this therapeutic target, especially in the subset of IBD patients with CD8+ T-cell dysfunction. Total RNA from distal colons of 8 week-old male wildtype C57Bl/6 and TNFR2-/- mice (n=3 each) was isolated using the PureLink RNA kit (Ambion, Life Technologies). RNA samples were submitted to the Genomic Services Lab at the HudsonAlpha Institute for Biotechnology (Huntsville, AL) for multiplex library preparation, mRNA enrichment, and sequencing. Sequencing was performed to an average depth of 50M paired-end 50bp reads per sample (HiSeq, Illumina, San Diego, CA). Data files containing raw reads were aligned to the mouse genome using Tophat2/Bowtie2. Alignments were assembled into transcript representations with Cufflinks, and statistical tests for differential expression were performed with Cuffdiff 2. An adjusted P value < 0.05 (q<0.05) from the Cuffdiff 2 output was used as the cutoff for statistical significance.
2015-08-11 | E-GEOD-65408 | biostudies-arrayexpress
Project description:T0001 is a recombinant human TNFR-Fc fusion protein mutant; it exhibits higher affinity to TNFα than etanercept and is now being tested in a Phase 1 study in China (ClinicalTrials.gov Identifier: NCT02481180). T0001 can inhibit the binding of soluble TNFα (sTNFα) or membrane-bound TNFα (mTNFα) to TNF receptors. When bound to mTNFα, the Fc-bearing TNFα antagonists have the potential to induce Fc-mediated effects, such as antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC) as well as outside-to-inside signals (apoptosis mainly). Recent studies have shown that ADCC may also play an important role in Crohn's disease (CD) and ulcerative colitis (UC). In this study, T0001 presented a higher binding activity on mTNFα than etanercept and similar binding activity with adalimumab and infliximab. Upon the addition of sTNFα, adalimumab and infliximab showed significantly increased binding to FcγRIIIa and C1q than T0001 and etanercept. T0001 exhibited significantly higher ADCC and CDC activity than etanercept, and the potency and the reporter response of T0001 were very close to adalimumab and infliximab in ADCC reporter gene assays. And the similar potency of T0001 was also corroborated by PMBC-based ADCC assay. T0001, but not etanercept could induce apoptosis, while adalimumab and infliximab were more effective. These results suggest that T0001 may not only exert improved efficacy in treating rheumatoid arthritis (RA) because of its high affinity to sTNFα but also has a therapeutic potential in CD and UC due to its increased binding to mTNFα with resultant Fc-associated functions (ADCC, in particular) and improved apoptosis.
| S-EPMC5438113 | biostudies-literature
Project description:Differentiation blockage can cause expansion of myeloid-derived suppressor cells (MDSCs) with ageing. Cell polarity loss (apolarity) in old stem or progenitor cells prevents their differentiation; but whether and how cell polarity is lost in old MDSCs, subsequently affecting their mature differentiation remains elusive. Here, we show that TNFR2 upregulation in old MDSCs triggers JNK over-activation, resulting in apolarity, differentiation blockage, and expansion of MDSCs with ageing. We find that TNFR2 expression in MDSCs can be induced by pro-inflammatory factors of senescence-associated secretory phenotype (SASP) and Tnfr2 deficiency in old mice significantly attenuates MDSCs’ differentiation blockage. Elevating TNFR2 expression in young MDSCs can induce apolarity and impair their differentiation; whereas suppressing JNK activity in old MDSCs can partially reverse their polarity and restore their differentiation capability. Therefore, TNFR2 aberrant upregulation represents a general mechanism by which extrinsic SASP signals dysregulate intrinsic cell polarity behaviors to arrest MDSCs’ mature differentiation during ageing.
2024-06-20 | GSE234791 | GEO
Project description:PURPOSE: The goal of this study was to determine the gene expression networks regulated by tumor necrosis factor receptor 2 (TNFR2, or Tnfrsf1b) and to evaluate their potential bearing on immune cell subsets and inflammatory bowel disease (IBD). METHODS: mRNA-seq was performed on isolated distal colons from TNFR2-knockout and wildtype mice. Differentially expressed transcripts were compared to human ulcerative colitis microarray datasets on Gene Expression Omnibus and to mouse immunological expression datasets at the Immunological Genome Project. RESULTS: We identified 252 mouse transcripts whose expressions were significantly altered by the loss of TNFR2. The majority of these transcripts (228 of 252, ~90%) were downregulated in TNFR2-/- colons. TNFR2-regulated genes were able to positively discriminate between ulcerative colitis patients and healthy individuals with ~80% accuracy. Many TNFR2-regulated genes were also highly expressed in CD8+ T cells. CONCLUSIONS: Downregulation of TNFR2 is associated with a gene expression profile that is prominent in IBD and supportive of the role of CD8+ T cells in IBD pathogenesis. MANUSCRIPT ABSTRACT: Increased tumor necrosis factor (TNF) production has been associated with inflammatory bowel disease (IBD), and anti-TNF therapy is a common therapeutic for this patient population. However, the role of TNF or its receptors (TNFR1 and TNFR2) in the immunopathogenesis of inflammatory bowel disease (IBD) remains unclear. Here we report that TNFR2 is protective in spontaneous (IL-10 knockout) and chemically (azoxymethane/dextran sodium sulfate)-induced mouse models of colitis and colitis-associated cancer. Mechanistically, TNFR2-deficiency in hematopoietic cells significantly increased incidence and severity of colitis and colitis-associated cancer characterized by a selective expansion of CD8+ T cells. We identified TNFR2-regulated genes in the colon that were specific for CD8+ T cells, interacted with multiple IBD risk genes, and are important regulators of CD8+ T cell biology. TNFR2 regulated CD8+ T-cell-specific genes that act as genetic susceptibility modifiers for IBD to mitigate the development of a pro-colitogenic milieu. Antibody-mediated depletion of CD8+ T cells prevented colonic inflammation and significantly reduced pathology in IL10-/-/TNFR2-/- deficient mice. Furthermore, adoptive transfer of TNFR2-/- naïve CD8+ T cells resulted in more severe disease than with wildtype naïve CD8+ T cells. Our findings provide insight into the disease modifier role of TNFR2 in the immunopathogenesis of IBD through the modulation of CD8+ T cell responses and support future investigation of this therapeutic target, especially in the subset of IBD patients with CD8+ T-cell dysfunction.
2015-08-11 | GSE65408 | GEO
Project description:Tumor necrosis factor receptor 2 (TNFR2), a membrane-bound tumor necrosis factor receptor expressed by regulatory T cells (Tregs), participates in Treg proliferation. Although a specific TNFR2 pathway has been reported, the signaling mechanism has not been completely elucidated. This study sought to clarify TNFR2 signaling in human Tregs using amplicon sequencing and single-cell RNA-sequencing to assess Tregs treated with a TNFR2 agonist antibody. Pathway enrichment analysis based on differentially expressed genes highlighted tumor necrosis factor α signaling via nuclear factor-kappa B, interleukin-2 signal transducer and activator of transcription 5 signaling, interferon-γ response, and cell proliferation-related pathways in Tregs after TNFR2 activation. TNFR2-high Treg-focused analysis found that these pathways were fully activated in cancer Tregs, showing high TNFR2 expression. Collectively, these findings suggest that TNFR2 orchestrates multiple pathways in cancer Tregs, which could help cancer cells escape immune surveillance, making TNFR2 signaling a potential anticancer therapy target.
2022-01-10 | GSE185145 | GEO
Project description:Control, TNFα and TNFα+JNK I treated GSCs
| PRJNA799754 | ENA