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Tumor Microenvironment Profiling Identifies Prognostic Signatures and Suggests Immunotherapeutic Benefits in Neuroblastoma

ABSTRACT: Tumor Microenvironment Profiling Identifies Prognostic Signatures and Suggests Immunotherapeutic Benefits in Neuroblastoma

PROVIDER: PRJNA756972 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15566578_1.fastq.gz	Fastqsanger.gz
	SRR15566578_2.fastq.gz	Fastqsanger.gz
	SRR15566579_1.fastq.gz	Fastqsanger.gz
	SRR15566579_2.fastq.gz	Fastqsanger.gz
	SRR15566580_1.fastq.gz	Fastqsanger.gz

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Tumor Microenvironment Profiling Identifies Prognostic Signatures and Suggests Immunotherapeutic Benefits in Neuroblastoma

Project description:Here, we profiled the TME landscape of 498 NB patients on a self-curated gene list and identified 3 prognostic TMEsubgroups. Differentially expressed genes (DEGs) among 3 TMEsubgroups constructed a genetic background of the TME landscape and characterized 3 GeneSubgroups. We further created a 48-gene signature, the TMEscore, to infer prognosis and validated in 3 independent NB cohorts and a pan-cancer cohort of 9460 patients. We did RNA-seq on 16 samples and verified that TMEscore was higher in stage 3/4 patients.

2021-09-10 | GSE182586 | GEO

Tumor Microenvironment Profiling Identifies Prognostic Signatures and Suggests Immunotherapeutic Benefits in Neuroblastoma.

Project description:The tumor microenvironment (TME) influences disease initiation and progression. Cross-talks of cells within TME can affect the efficacy of immunotherapies. However, a precise, concise, and comprehensive TME landscape in neuroblastoma (NB) has not been established. Here, we profiled the TME landscape of 498 NB-related patients on a self-curated gene list and identified three prognostic TMEsubgroups. The differentially expressed genes in these three TMEsubgroups were used to construct a genetic signature of the TME landscape and characterize three GeneSubgroups. The subgroup with the worst overall survival prognosis, the TMEsubgroup/GeneSubgroup3, lacked immune cell infiltration and received the highest scores of MYCN- and ALK-related signatures and lowest scores of immune pathways. Additionally, we found that the GeneSubgroup3 might be benefited from anti-GD2 instead of anti-PD-1 therapy. We further created a 48-gene signature, the TMEscore, to infer prognosis and validated it in three independent NB cohorts and a pan-cancer cohort of 9,460 patients. We did RNA-seq on 16 samples and verified that TMEscore was higher in patients with stage 3/4 than stage 1/2 diseases. The TMEscore could also predict responses for several immunotherapies. After adding clinical features, we found that the nomogram-based score system, the TMEIndex, surpassed the current risk system at predicting survivals. Our analysis explained TME at the transcriptome level and paved the way for immunotherapies in NB.

| S-EPMC9047956 | biostudies-literature

A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma

Project description:Cancer immunotherapies have produced remarkable results in B-cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor specimens along with normal tissues to identify biologically relevant cell surface proteins that can serve as immunotherapeutic targets for neuroblastoma, the often fatal childhood cancer of the developing nervous system. We apply this approach to human-derived cell lines (N=9) and cell/patient-derived xenograft (N=12) models of neuroblastoma. Plasma membrane-enriched mass spectrometry identified 1,461 cell surface proteins in cell lines and 1,401 in xenograft models, respectively. Additional proteogenomic analyses revealed 71 high-confidence candidate immunotherapeutic targets and we prioritized Delta-like canonical notch ligand 1 (DLK1) for further study. High expression of DLK1 directly correlated with the presence of a super-enhancer spanning the DLK1 locus. Robust cell surface expression of DLK1 was validated by immunofluorescence, flow cytometry, and immunohistochemistry. Short hairpin RNA mediated silencing of DLK1 in neuroblastoma cells resulted in increased cellular differentiation. ADCT-701, a DLK1-targeting antibody-drug conjugate (ADC), showed potent and specific cytotoxicity in DLK1-expressing neuroblastoma xenograft models. Finally, we also found that DLK1 is highly expressed in several adult cancer types including adrenocortical carcinoma (ACC), pheochromocytoma/paraganglioma (PCPG) and small cell lung cancer (SCLC) suggesting potential clinical benefit beyond neuroblastoma. A clinical trial has been developed for evaluating ADCT-701 in neuroendocrine tumors in adults (https://www.clinicaltrials.gov/study/NCT06041516?term=adct-701&rank=1). Therefore, comprehensive characterization of cancer surfaceomes can provide biologically relevant immunotherapy targeting strategies.

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XPO1/CRM1 is a promising prognostic indicator for neuroblastoma and represented a therapeutic target by selective inhibitor KPT-335.

Project description:The five-year survival rate remains less than 50% for high-risk neuroblastoma patients, few of them show effective response to current chemotherapy drugs. It is urgent to identify new therapeutic targets and corresponding drugs for high-risk neuroblastoma. Exportin-1(XPO1), also known as chromosomal region maintenance 1 (CRM1), plays important roles in the progress of tumorigenesis. However, the prognostic and therapeutic values of XPO1 in neuroblastoma have not been reported. Here, our results showed that overexpression of XPO1 was significantly associated with poor clinical characteristics and prognosis of neuroblastoma patients. The specific inhibitor of XPO1 suppressed neuroblastoma cell growth both in vitro and in vivo. Specifically, inhibition of XPO1 suppressed neuroblastoma cells proliferation and induced cell apoptosis by FOXO1 and RB1 nuclear accumulation in neuroblastoma through inhibiting PI3K/AKT pathway, and induced G0/G1 phase cell arrest by activating P53 function. Together, XPO1 is a promising prognostic indicator for neuroblastoma and a novel target for antitumor treatment by selective inhibitor verdinexor (KPT-335).

2021-08-18 | GSE163987 | GEO

Transcription profiling of human prognostic samples from neuroblastoma patients for classification of neuroblastoma by integrating gene expression pattern with regional alterations in DNA copy number

Project description:The specific genes that influence neuroblastoma biology and are targeted by genomic alterations remain largely unknown. We quantified mRNA expression in a highly annotated series of 101 prospectively collected diagnostic neuroblastoma primary tumors and the expression profiles were determined using Affymetrix U95Av2 arrays. Comparisons between the sample groups allow the identification of genes with localized expression patterns. This study demonstrates that the genomic data can be used to subcategorize the disease into molecular subsets and the regional copy number alterations are correlated with a broad number of transcriptional alterations genome wide. This data also suggests that multiple genes from several discrete regions of the human genome co-operate to supress neuroblastoma tumorigenesis and progression. Experiment Overall Design: A highly annotated series of 101 prospectively collected diagnostic neuroblastoma primary tumors were selected to quantify mRNA expression using an oligonucleotide based microarray. Genomic copy number status at the prognostically relevant loci 1p36,2p24(MYCN), 11q23 and 17q23 was determined by PCR and was aberrant in 26, 20, 40 and 38 cases, respectively. Fetal brain RNA was used as a control sample.

2008-06-12 | E-GEOD-3960 | biostudies-arrayexpress

DHODH is an independent prognostic marker and potent therapeutic target in neuroblastoma

Project description:DHODH is an independent prognostic marker and potent therapeutic target in neuroblastoma

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Telomerase is a prognostic marker of poor outcome and a therapeutic target in neuroblastoma

Project description:The aim of this study is to determine the clinical relevance of telomerase activation versus ALT as biomarkers in pre-treatment neuroblastoma, and to assess the potential value of telomerase as a therapeutic target. Therefore, the genomic status of TERT and MYCN was assessed in 457 pretreatment neuroblastomas by fluorescence-in-situ-hybridization. ALT was examined in 273/457 tumors by detection of ALT-associated promyelocytic leukemia nuclear bodies, and TERT expression was determined by 4x44k microarrays in 223 of these. The presence of activated telomerase, i.e., TERT rearrangements, MYCN amplification, or high TERT expression without these alterations, was associated with poorest overall survival, and was an independent prognostic marker in multivariable analyses.

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Project description:In this study, mRNA expression profiles of 113 primary untreated human neuroblastoma samples were compared with the aim to identify prognostic exon and gene sets as well as parameters associated with alternative exon use. The primary neuroblastoma specimens were from tumor banks in Cologne or Essen, Germany, Ghent, Belgium and Valencia, Spain. All patients were diagnosed between 1998 and 2007 and treated according to the German Neuroblastoma trials NB97, NB 2004 or the SIOPEN protocol.

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Epigenetic state determines inflammatory sensing in neuroblastoma [RNA-seq]

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