Immuno-genomic landscape of osteosarcoma

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Feb. 21, 2020

Abstract Limited clinical activity has been seen in osteosarcoma (OS) patients treated with immune checkpoint inhibitors (ICI). To gain insights into the immunogenic potential of these tumors, we conducted whole genome, RNA, and T-cell receptor sequencing, immunohistochemistry reverse phase protein array profiling (RPPA) on OS specimens from 48 pediatric adult primary, relapsed, metastatic OS. Median infiltrate level was lower than other tumor types where ICI are effective, concomitant low clonalities. Neoantigen expression lacking significantly associated high levels nonsense-mediated decay (NMD). Samples had higher number deleted genes while those expressed adaptive resistance pathways. PARP2 were negatively infiltrate. Together, data reveal multiple immunosuppressive features suggest immunotherapeutic opportunities patients.

Language: Английский

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Immune-Related lncRNA to Construct Novel Signature and Predict the Immune Landscape of Human Hepatocellular Carcinoma

Molecular Therapy — Nucleic Acids, Journal Year: 2020, Volume and Issue: 22, P. 937 - 947

Published: Oct. 10, 2020

The signature composed of immune-related long noncoding ribonucleic acids (irlncRNAs) with no requirement specific expression level seems to be valuable in predicting the survival patients hepatocellular carcinoma (HCC). Here, we retrieved raw transcriptome data from Cancer Genome Atlas (TCGA), identified irlncRNAs by co-expression analysis, and recognized differently expressed irlncRNA (DEirlncRNA) pairs using univariate analysis. In addition, modified Lasso penalized regression. Then, compared areas under curve, counted Akaike information criterion (AIC) values 5-year receiver operating characteristic cut-off point set up an optimal model for distinguishing high- or low-disease-risk groups among HCC. We then reevaluated them viewpoints survival, clinic-pathological characteristics, tumor-infiltrating immune cells, chemotherapeutics efficacy, immunosuppressed biomarkers. 36 DEirlncRNA were identified, 12 which included a Cox regression model. After regrouping point, could more effectively differentiate between based on unfavorable outcome, aggressive tumor infiltration status, low sensitivity, highly established paring regardless levels showed promising clinical prediction value.

Language: Английский

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Cell Clustering Promotes a Metabolic Switch that Supports Metastatic Colonization

Cell Metabolism, Journal Year: 2019, Volume and Issue: 30(4), P. 720 - 734.e5

Published: Aug. 22, 2019

Cancer metastasis depends on cell survival following loss of extracellular matrix attachment and dissemination through the circulation. The metastatic spread can be enhanced by clustering detached cancer cells increased antioxidant defense. Here, we link these responses describing how limits reactive oxygen species (ROS). Loss causes mitochondrial perturbations ROS production. formation clusters induces a hypoxic environment that drives hypoxia-inducible factor 1-alpha (Hif1α)-mediated mitophagy, clearing damaged mitochondria limiting ROS. However, hypoxia reduced capacity promote dependence glycolysis for ATP production is supported cytosolic reductive metabolism. Preventing this metabolic adaptation or disruption results in accumulation, death, reduction vivo. Our provide mechanistic explanation role supporting during detachment may point to targetable vulnerabilities.

Language: Английский

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Therapeutically Increasing MHC-I Expression Potentiates Immune Checkpoint Blockade

Cancer Discovery, Journal Year: 2021, Volume and Issue: 11(6), P. 1524 - 1541

Published: Feb. 15, 2021

Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but many patients with impaired MHC-I expression remain refractory. Here, we combined FACS-based genome-wide CRISPR screens a data-mining approach to identify drugs that can upregulate without inducing PD-L1. screening identified TRAF3, suppressor of the NFκB pathway, as negative regulator not The Traf3-knockout gene signature is associated better survival in ICB-naïve and ICB response. We then screened for similar transcriptional effects this Second Mitochondria-derived Activator Caspase (SMAC) mimetics. experimentally validated SMAC mimetic birinapant upregulates MHC-I, sensitizes cells T cell-dependent killing, adds efficacy. Our findings provide preclinical rationale treating tumors expressing low mimetics enhance sensitivity immunotherapy. used study be generalized other immunotherapy SIGNIFICANCE: loss or downregulation major mechanism resistance cell-based immunotherapies. reveals may baseline This represents promising opportunities given biosafety profile from multiple clinical trials.This article highlighted In Issue feature, p. 1307.

Language: Английский

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Hiplot: a comprehensive and easy-to-use web service for boosting publication-ready biomedical data visualization

Briefings in Bioinformatics, Journal Year: 2022, Volume and Issue: 23(4)

Published: July 5, 2022

Abstract Complex biomedical data generated during clinical, omics and mechanism-based experiments have increasingly been exploited through cloud- visualization-based mining techniques. However, the scientific community still lacks an easy-to-use web service for comprehensive visualization of data, particularly high-quality publication-ready graphics that allow easy scaling updatability according to user demands. Therefore, we propose a community-driven modern service, Hiplot (https://hiplot.org), with concise top-quality applications life sciences fields. This permits users conveniently interactively complete few specialized tasks previously could only be conducted by senior bioinformatics or biostatistics researchers. It covers most daily demands researchers its equipped 240+ functions, involving basic statistics, multi-omics, regression, clustering, dimensional reduction, meta-analysis, survival analysis, risk modelling, etc. Moreover, improve efficiency in use development plugins, introduced some core advantages on client-/server-side website, such as spreadsheet-based importing, cross-platform command-line controller (Hctl), multi-user plumber workers, JavaScript Object Notation-based plugin system, data/parameters, results errors reproduction real-time updates mode. Meanwhile, using demo/real sets benchmark tests, explored statistical parameters, cancer genomic landscapes, disease factors performance website based selected native plugins. The statistics visits numbers further reflect potential impact this relevant Thus, devoted would benefit from emerging free service.

Language: Английский

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