Tumor cell intrinsic RIG-I activation is sufficient to drive immune mediated tumor rejection
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE221564 | GEO | 2025/11/28
REPOSITORIES: GEO
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Project description:Tumor cell intrinsic RIG-I activation is sufficient to drive immune mediated tumor rejection
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Project description:We have developed highly potent synthetic activators of the vertebrate immune system that specifically target the RIG-I receptor. When introduced into mice, a family of short, triphosphorylated Stem Loop RNAs (SLRs) induces a potent interferon response and the activation of specific genes essential for antiviral defense. Using RNAseq, we provide the first in-vivo genome-wide view of the expression networks that are initiated upon RIG-I activation. We observe that SLRs specifically induce type I interferons, subsets of interferon-stimulated genes (ISGs), and cellular remodeling factors. By contrast, poly(I:C), which binds and activates multiple RNA sensors, induces type III interferons and several unique ISGs. The short length (10-14 base pairs) and robust function of SLRs in mice demonstrate that RIG-I forms active signaling complexes without oligomerizing on RNA. These findings demonstrate that SLRs are potent therapeutic and investigative tools for targeted modulation of the innate immune system.
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Project description:We identified a small molecule compound, KIN1148, that directly binds RIG-I to drive IRF3 and NF B activation and expression of innate immune genes, cytokines and chemokines. KIN1148 activates RIG-I in an RNA- and ATP-independent manner and does not induce a canonical antiviral interferon (IFN) gene program traditionally associated with RIG-I activation. When administered in combination with a vaccine against influenza A virus (IAV), KIN1148 induces both neutralizing antibody and broadly cross-protective IAV-specific T cell responses compared to vaccination alone, which induces poor responses. In this study, we demonstrate that KIN1148 directly engages RIG-I to activate IRF3- and NFB-dependent innate immune responses, making it the first small molecule RIG-I agonist to be identified. Biochemical studies show that KIN1148 binds to RIG-I to drive RIG-I self-oligomerization and downstream signaling activation in an RNA- and ATP-independent manner. We further find that transcriptional programs induced by KIN1148 treatment exhibit shared and unique signatures to that induced by other methods of RIG-I activation, including Sendai virus (SeV) infection and PAMP RNA transfection. KIN1148 adjuvants a split virus (SV) vaccine at suboptimal dose to protect mice from lethal challenge with a recombinant highly pathogenic avian H5N1 influenza virus, A/Vietnam/1203/2004.
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Project description:Transcriptional profiling of chicken embryonic fibroblasts (DF-1 cells) comparing the effects of chicken cells transfected with duck RIG-I compared to empty-vector transfected cells following with low or highly pathogenic avian influenza. Goal was to determine the effects of duck RIG-I on influenza-induced immune gene expression. Two-condition experiment. Biological replicates for low pathogenic avian influenza infection: 3 empty-vector transfected replicates, 3 RIG-I transfected replicates. Biological replicates for highly pathogenic influenza infection: 2 empty-vector transfected replicates, 2 RIG-I transfected replicates.
2012-12-12 | E-GEOD-29596 | biostudies-arrayexpress
Project description:We performed RNAseq analysis on WT and LGP2-/- BM-DCs treated with a RIG-I agonist (HCV Poly-U/C RNA) to understand how LGP2 impacts global transcriptional changes following activation of the RIG-I pathway. Analysis of the transcriptional profiles revealed that LGP2 functions as a negative regulator of RIG-I signaling as early as 1 hours post-RIG-I agonist treatment. This finding led us to study how LGP2 negatively influences RIG-I activation through post-translational modification.
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Project description:Maintaining innate immune homeostasis is critical for preventing infections and autoimmune diseases, but the effective interventions are lacking. Here, we identified Cys864-Cys869-mediated intermolecular disulfide-linkage formation as a critical step for human RIG-I activation that can be bidirectionally regulated to control innate immune homeostasis. The viral-stimulated Cys864-Cys869 disulfide-linkage mediates conjugation of an SDS-resistant RIG-I oligomer, which prevents RIG-I degradation by E3 ubiquitin-ligase MIB2 and is necessary for RIG-I to perform liquid-liquid phase separation to compartmentalize downstream signalsome, thereby stimulating IFN-I signaling. The corresponding C865S ‘knock-in’ caused defect of oligomerization and LLPS in mouse RIG-I, which inhibited innate immunity, resulting in increased viral load and mortality in mice. Through generating covalent Cys864-Cys869 linkage by unnatural amino-acid and developing interfering peptide to block Cys864-Cys869 residues, we bidirectionally regulate RIG-I activities in human diseases. These findings provide novel and in-depth insights on mechanism of RIG-I activation, develop methodologies that hold promising implications in clinics
2024-12-09 | GSE283490 | GEO
Project description:The RIG-I like receptor pathway is stimulated during RNA virus infection by interaction between cytosolic RIG-I and viral RNA structures that contain short hairpin dsRNA and 5M-bM-^@M-^Y triphosphate (5M-bM-^@M-^Yppp) terminal structure. In the present study, an RNA agonist of RIG-I was synthesized in vitro and shown to stimulate RIG-I-dependent antiviral responses at concentrations in the picomolar range. In human lung epithelial A549 cells, 5M-bM-^@M-^YpppRNA specifically stimulated multiple parameters of the innate antiviral response, including IRF3, IRF7 and STAT1 activation, andinduction of inflammatory and interferon stimulated genes - hallmarks of a fully functional antiviral response. Evaluation of the magnitude and duration of gene expression by transcriptional profiling identified a robust, sustained and diversified antiviral and inflammatory response characterized by enhanced pathogen recognition and interferon (IFN)signaling. Bioinformatics analysis further identified a transcriptional signature uniquely induced by 5M-bM-^@M-^YpppRNA, and not by IFNM-NM-1-2bthat included a constellation of IRF7 and NF-kB target genes capable of mobilizing multiple arms of the innate and adaptive immune response. Treatment of primary PBMCs or lung epithelial A549 cells with 5M-bM-^@M-^YpppRNA provided significant protection against a spectrum of RNA and DNA viruses. In C57Bl/6 mice, intravenous administration of 5M-bM-^@M-^YpppRNA protected animals from a lethal challenge with H1N1 Influenza, reduced virus titers in mouse lungs and protected animals from virus-induced pneumonia. Strikingly, the RIG-I-specific transcriptional response afforded partial protection from influenza challenge, even in the absence of type I interferon signaling. This systems approach providestranscriptional, biochemical, and in vivo analysis of the antiviral efficacy of 5M-bM-^@M-^YpppRNA and highlights the therapeutic potential associated with the use of RIG-I agonists as broad spectrum antiviral agents. Kinetic analysis of A549 cells treated with 5'pppRNA and analyzed at 1h, 2h, 4h, 6h, 8h, 12h, 24h or 48h.
2014-08-21 | E-GEOD-60573 | biostudies-arrayexpress
Project description:The RIG-I like receptor pathway is stimulated during RNA virus infection by interaction between cytosolic RIG-I and viral RNA structures that contain short hairpin dsRNA and 5M-bM-^@M-^Y triphosphate (5M-bM-^@M-^Yppp) terminal structure. In the present study, an RNA agonist of RIG-I was synthesized in vitro and shown to stimulate RIG-I-dependent antiviral responses at concentrations in the picomolar range. In human lung epithelial A549 cells, 5M-bM-^@M-^YpppRNA specifically stimulated multiple parameters of the innate antiviral response, including IRF3, IRF7 and STAT1 activation, andinduction of inflammatory and interferon stimulated genes - hallmarks of a fully functional antiviral response. Evaluation of the magnitude and duration of gene expression by transcriptional profiling identified a robust, sustained and diversified antiviral and inflammatory response characterized by enhanced pathogen recognition and interferon (IFN)signaling. Bioinformatics analysis further identified a transcriptional signature uniquely induced by 5M-bM-^@M-^YpppRNA, and not by IFNM-NM-1-2bthat included a constellation of IRF7 and NF-kB target genes capable of mobilizing multiple arms of the innate and adaptive immune response. Treatment of primary PBMCs or lung epithelial A549 cells with 5M-bM-^@M-^YpppRNA provided significant protection against a spectrum of RNA and DNA viruses. In C57Bl/6 mice, intravenous administration of 5M-bM-^@M-^YpppRNA protected animals from a lethal challenge with H1N1 Influenza, reduced virus titers in mouse lungs and protected animals from virus-induced pneumonia. Strikingly, the RIG-I-specific transcriptional response afforded partial protection from influenza challenge, even in the absence of type I interferon signaling. This systems approach providestranscriptional, biochemical, and in vivo analysis of the antiviral efficacy of 5M-bM-^@M-^YpppRNA and highlights the therapeutic potential associated with the use of RIG-I agonists as broad spectrum antiviral agents. A549 cells were either non-treated, treated with RNAiMax only, transfected with 5'pppRNA, or treated with IFNa-2b and analysed at 6h or 24h.
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Project description:Tumor cells often employ many ways to restrain type I interferon (IFN-I) signaling to evade immune surveillance. However, whether cellular amino acid metabolism regulate this process remains unclear and its effects on antitumor immunity are relatively unexplored. Here, our study reports that asparagine generated by asparagine synthetase (ASNS) inhibits IFN-I signaling and promotes immune escape in bladder cancer. We further show that depletion of ASNS strongly limits in vivo tumor growth in a CD8+ T cell-dependent manner, thus boosting the immunotherapy efficacy. Moreover, clinically approved ASNase synergizes with anti-PD-1 therapy in suppressing tumor growth in mouse models of bladder cancer. Mechanistically, asparagine intensifies the interaction of E3 ligase CBL and RIG-I, promoting K48-linked polyubiquitination and degradation of RIG-I, thus suppressing RIG-I mediated IFN signaling and anti-tumor immune response. Clinically, ASNS is overexpressed in muscle-invasive bladder cancer and correlated with poor response of immunotherapy. Together, our findings uncover asparagine as a natural metabolite to modulate RIG-I-mediated IFN-I signaling, providing the basis for developing the combinatorial use of ASNase and anti-PD-1 for bladder cancer.
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