Universal STING Mimic Boosts Antitumour Immunity via Preferential Activation of Tumour Control Signalling Pathways
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ABSTRACT:
PROVIDER: PRJNA1066759 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR27646836_1.fastq.gz | Fastqsanger.gz | |||
| SRR27646836_2.fastq.gz | Fastqsanger.gz | |||
| SRR27646837_1.fastq.gz | Fastqsanger.gz | |||
| SRR27646837_2.fastq.gz | Fastqsanger.gz | |||
| SRR27646838_1.fastq.gz | Fastqsanger.gz |
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Project description:Universal STING Mimic Boosts Antitumour Immunity via Preferential Activation of Tumour Control Signalling Pathways
| PRJNA1066825 | ENA
Project description:The efficacy of stimulator of interferon genes (STING) agonists is compromised by various factors, primarily inefficient intracellular delivery, low/lack of endogenous STING expression in many tumours and a complex balance between tumour control and progression. Here, we report a universal STING mimic (uniSTING) based on a polymeric architecture. The uniSTING activates STING signalling in a range of mouse and human cell types, independent of endogenous STING expression, and selectively stimulates tumour control IRF3/IFN-I pathways, but not tumour progression NF-κB pathways. Intratumoural or systemic injection of uniSTING-mRNA via lipid nanoparticles (LNP) results in potent anti-tumour efficacy across established and advanced metastatic tumour models, including triple negative breast cancer, lung cancer, melanoma and orthotopic/metastatic liver malignancies. Furthermore, uniSTING displays an effective antitumour response superior to 2’3’-cGAMP and ADU-S100. By favouring IRF3/IFN-I activity over the pro-inflammatory NF-κB signalling pathway, uniSTING promotes dendritic cell maturation and antigen specific CD8+ T cell responses. Extracellular vesicles released from uniSTING-treated tumour cells further sensitise dendritic cells via exosome containing miRNAs that reduced the immunosuppressive Wnt2b and a combination of LNP-uniSTING-mRNA with α-Wnt2b antibodies synergistically inhibit tumour growth and prolong animal survival. Collectively, these results demonstrate the LNP-mediated delivery of uniSTING-mRNA as a strategy to overcome the current STING therapeutic barriers, particularly for the treatment of multiple cancer types in which STING is downregulated or absent.
2024-01-24 | GSE253681 | GEO
Project description:The efficacy of stimulator of interferon genes (STING) agonists is compromised by various factors, primarily inefficient intracellular delivery, low/lack of endogenous STING expression in many tumours and a complex balance between tumour control and progression. Here, we report a universal STING mimic (uniSTING) based on a polymeric architecture. The uniSTING activates STING signalling in a range of mouse and human cell types, independent of endogenous STING expression, and selectively stimulates tumour control IRF3/IFN-I pathways, but not tumour progression NF-κB pathways. Intratumoural or systemic injection of uniSTING-mRNA via lipid nanoparticles (LNP) results in potent anti-tumour efficacy across established and advanced metastatic tumour models, including triple negative breast cancer, lung cancer, melanoma and orthotopic/metastatic liver malignancies. Furthermore, uniSTING displays an effective antitumour response superior to 2’3’-cGAMP and ADU-S100. By favouring IRF3/IFN-I activity over the pro-inflammatory NF-κB signalling pathway, uniSTING promotes dendritic cell maturation and antigen specific CD8+ T cell responses. Extracellular vesicles released from uniSTING-treated tumour cells further sensitise dendritic cells via exosome containing miRNAs that reduced the immunosuppressive Wnt2b and a combination of LNP-uniSTING-mRNA with α-Wnt2b antibodies synergistically inhibit tumour growth and prolong animal survival. Collectively, these results demonstrate the LNP-mediated delivery of uniSTING-mRNA as a strategy to overcome the current STING therapeutic barriers, particularly for the treatment of multiple cancer types in which STING is downregulated or absent.
2024-01-22 | GSE253724 | GEO
Project description:Universal STING Mimic Boosts Antitumour Immunity via Preferential Activation of Tumour Control Signalling Pathways
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Project description:We found that PROCR promotes IL-6 secretion, which is magnified after radiation, leading to inhibition of antitumour immunity. Next, we investigated the mechanism by which PROCR upregulated IL-6. To this end, we performed RNA sequencing on irradiated HONE1 cells with or without PROCR knockout.
2025-05-29 | GSE282897 | GEO
Project description:The gut microbiota is related to the antitumour efficacy of immune checkpoint blockade, but the mechanism(s) of action have not been fully elucidated. Here, we show that a novel Ruminococcaceae strain (designated YB328) isolated from the faeces of patients who responded to programmed cell death 1 (PD-1) blockade primes/activates tumour-specific CD8+ T cells through stimulation/maturation of CD103+CD11b- conventional dendritic cells (cDCs) which migrate from the gut to the tumour microenvironment (TME). YB328 administration improved the antitumour efficacy of PD-1 blockade even when it was added to faecal transplantation from non-responder patients in animal models. YB328 promoted the IRF8-driven differentiation of CD103+CD11b- cDCs expressing multiple Toll-like receptors, which received additional stimulation/maturation signals from other bacteria, and the accumulation of these DCs in tumour lesions. These CD103+CD11b- cDCs prolonged engagement with cognate antigen-specific CD8+ T cells, which induced the activation of CD8+ T cells specific for diverse tumour antigens and fostered PD-1 expression through NFATc1 nuclear translocation, thereby leading to an increase in PD-1+CD8+ T cells harbouring a broader T-cell receptor repertoire in the TME. We propose that the gut microbiota augments antitumour immunity by accelerating the differentiation/maturation and migration of DCs to increase CD8+ T cells responding to diverse tumour antigens.
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