Systemically administered HMGN1 immunostimulatory peptide with anti-PD-L1 antibody exerts synergistic antitumor effects
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ABSTRACT:
PROVIDER: PRJNA579156 | ENA |
REPOSITORIES: ENA
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Project description:In this study, we explore a new combination therapy of anti-PD-L1 antibody with an immunostimulatory peptide derived from an alarmin high mobility group nucleosome binding protein 1 (HMGN1). Combination treatement of HMGN1 immunostimulatory peptide with anti-PD-L1 antibody exerted robust anti-tumor effects in Colon26 subtaneous murine model. To understand transcriptomic differences of immune cell population in the tumor-bearing mice after treated with single-agent or combination therapy of HMGN1 with anti-PD-L1 antibody, we performed transcriptome analysis on tumor tissue using 5’end Serial Analysis of Gene Expression (SAGE)-sequencing with an Ion 540 Chef kit, an Ion 540 Chip kit, and an Ion S5 Sequencer (Thermo Fisher Scientific).
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Project description:Recently there has been growing interest in the immunomodulatory effects of endogenous danger signals known as alarmins. In this study, we explore a new combination therapy of anti-CD4 depleting antibody with an alarmin, high mobility group nucleosome binding protein 1 (HMGN1). Extremely low dose of HMGN1 with anti-CD4 depleting antibody exerted robust anti-tumor effects in Colon26 subtaneous murine model. To understand transcriptomic differences of CD8+ T cells in the tumor-bearing mice after treated with anti-CD4 depleting antibody or combination therapy of HMGN1 with anti-CD4 depleting antibody, we performed CD8 T cell transcriptome analysis using 3'SAGE-seq and Ion Proton sequencer.
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Project description:Systemically administered extremely low HMGN1 with anti-CD4 depleting antibody exerts synergistic anti-tumor effects
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Project description:In this study, we explore a new combination therapy of anti-PD-L1 antibody with an immunostimulatory peptide derived from an alarmin high mobility group nucleosome binding protein 1 (HMGN1). Combination treatment of HMGN1 immunostimulatory peptide (minP1) with anti-PD-L1 antibody exerted robust anti-tumor effects in the Colon26 subcutaneous murine model. To understand transcriptomic differences of the immune cell populations in the tumor-bearing mice after treatment with single-agent or combination therapy of minP1 with anti-PD-L1 antibody, we performed single-cell RNA sequencing (scRNA-seq) analysis on CD45+ immune cell populations using the BD Rapsody system, NEBNext UltraII FS library prep kit, and a Illumina Novaseq 6000 S4 flowcell.
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Project description:Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver MicroRNA-122 (miR-122) is an abundant liver-specific miRNA, implicated in fatty acid and cholesterol metabolism as well as hepatitis C viral replication. Here, we report that a systemically administered 16-nt, unconjugated LNA (locked nucleic acid)-antimiR oligonucleotide complementary to the 5' end of miR-122 leads to specific, dose-dependent silencing of miR-122 and shows no hepatotoxicity in mice. Antagonism of miR-122 is due to formation of stable heteroduplexes between the LNA-antimiR and miR-122 as detected by northern analysis. Fluorescence in situ hybridization demonstrated uptake of the LNA-antimiR in mouse liver cells, which was accompanied by markedly reduced hybridization signals for mature miR-122 in treated mice. Functional antagonism of miR-122 was inferred from a low cholesterol phenotype and de-repression within 24 h of 199 liver mRNAs showing significant enrichment for miR-122 seed matches in their 3' UTRs. Expression profiling extended to 3 weeks after the last LNA-antimiR dose revealed that most of the changes in liver gene expression were normalized to saline control levels coinciding with normalized miR-122 and plasma cholesterol levels. Combined, these data suggest that miRNA antagonists comprised of LNA are valuable tools for identifying miRNA targets in vivo and for studying the biological role of miRNAs and miRNA-associated gene-regulatory networks in a physiological context. Keywords: compound treatment
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Project description:Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver; MicroRNA-122 (miR-122) is an abundant liver-specific miRNA, implicated in fatty acid and cholesterol metabolism as well as hepatitis C viral replication. Here, we report that a systemically administered 16-nt, unconjugated LNA (locked nucleic acid)-antimiR oligonucleotide complementary to the 5' end of miR-122 leads to specific, dose-dependent silencing of miR-122 and shows no hepatotoxicity in mice. Antagonism of miR-122 is due to formation of stable heteroduplexes between the LNA-antimiR and miR-122 as detected by northern analysis. Fluorescence in situ hybridization demonstrated uptake of the LNA-antimiR in mouse liver cells, which was accompanied by markedly reduced hybridization signals for mature miR-122 in treated mice. Functional antagonism of miR-122 was inferred from a low cholesterol phenotype and de-repression within 24 h of 199 liver mRNAs showing significant enrichment for miR-122 seed matches in their 3' UTRs. Expression profiling extended to 3 weeks after the last LNA-antimiR dose revealed that most of the changes in liver gene expression were normalized to saline control levels coinciding with normalized miR-122 and plasma cholesterol levels. Combined, these data suggest that miRNA antagonists comprised of LNA are valuable tools for identifying miRNA targets in vivo and for studying the biological role of miRNAs and miRNA-associated gene-regulatory networks in a physiological context. Experiment Overall Design: Female NMRI mice were treated at day 2 with either 25mg/kg antimiR-122 (SPC3372) or vehicle (saline). Mice were sacrificied at day 3, 9 and 23 and liver RNA assayed. Three biological replicates for each of the six groups.
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Project description:Corticosteroids have been prescribed for decades to modulate inflammation, yet there is a paucity of data on their effects in humans. We examined the changes in cellular and molecular immune system parameters, or “immunome,” in 20 volunteers at baseline, and after intravenous hydrocortisone (HC) administered at moderate (250 mg) and low (50 mg) doses, to provide insight into how corticosteroids exert their effects. We observed declines in specific B and T cell subsets, and an increase in natural killer cell subsets 4-8 hours after HC. Whole transcriptome profiling revealed a gene expression signature that preceded lymphocyte population changes. We observed decreases in inflammatory cytokines after HC administration. Our study provides insights into the effects of corticosteroids on the human immunome.
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Project description:HMGN1 contributes to the shortened latency of liver tumorigenesis by changing a chromatin structure and expression of relevant genes To assess the molecular mechanisms underlying accelerated tumor development in Hmgn1-/- mice, we performed the gene expression profiling of liver cells at early stages Expression profiles has been compared between Hmgn1+/+ and Hmgn1-/- mice livers at 4 weeks after birth and at 12 weeks after DEN or saline (control) injection at 4 weeks
2013-08-24 | E-GEOD-44356 | biostudies-arrayexpress
Project description:High mobility group (HMG) proteins interact with other architectural proteins to regulate chromatin structure. We performed genome-wide mapping experiments to examine the distribution of HMGN1 across the human genome. We discovered that HMGN1 proteins are enriched at regulatory regions such as DNase I HS sites, distal transcription factor binding sites and promoters of actively transcribed genes. YY1, the Yin Yang 1 transcription factor, is a ubiquitous transcription factor that functions either as a transcriptional activator or a repressor, depending on its interacting partner. To test the preferential localization of HMGN1 with active regulatory regions, we examined the association of transcription factor YY1 and HMGN1 in CD4+ T cells. Examination of the genomic profile of HMGN1 and the relationship with regulatory elements in CD4+ T cells.
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