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Neuroblastoma Origin and Therapeutic Targets for Immunotherapy.

ABSTRACT: Neuroblastoma is a pediatric solid cancer of heterogeneous clinical behavior. The unique features of this type of cancer frequently hamper the process of determining clinical presentation and predicting therapy effectiveness. The tumor can spontaneously regress without treatment or actively develop and give rise to metastases despite aggressive multimodal therapy. In recent years, immunotherapy has become one of the most promising approaches to the treatment of neuroblastoma. Still, only one drug for targeted immunotherapy of neuroblastoma, chimeric monoclonal GD2-specific antibodies, is used in the clinic today, and its application has significant limitations. In this regard, the development of effective and safe GD2-targeted immunotherapies and analysis of other potential molecular targets for the treatment of neuroblastoma represents an important and topical task. The review summarizes biological characteristics of the origin and development of neuroblastoma and outlines molecular markers of neuroblastoma and modern immunotherapy approaches directed towards these markers.

SUBMITTER: Kholodenko IV

PROVIDER: S-EPMC6079467 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Neuroblastoma Origin and Therapeutic Targets for Immunotherapy.

Kholodenko Irina V IV Kalinovsky Daniel V DV Doronin Igor I II Deyev Sergey M SM Kholodenko Roman V RV

Journal of immunology research 20180711

Neuroblastoma is a pediatric solid cancer of heterogeneous clinical behavior. The unique features of this type of cancer frequently hamper the process of determining clinical presentation and predicting therapy effectiveness. The tumor can spontaneously regress without treatment or actively develop and give rise to metastases despite aggressive multimodal therapy. In recent years, immunotherapy has become one of the most promising approaches to the treatment of neuroblastoma. Still, only one dru ...[more]

PMID: 30116755

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Project description:BackgroundNeuroblastoma (NB) is a childhood cancer originating from immature nerve cells in the sympathetic nervous system. Current clinical and molecular subtyping methods for NB have limitations in providing accurate prognostic information and guiding treatment decisions.ResultsTo overcome these challenges, we explored the microenvironment of NB based on the knowledge-based functional gene expression signatures (Fges), which revealed heterogeneous subtypes. Consensus clustering of Fges activity scores identified three subtypes (Cluster 1, Cluster 2, and Cluster 3) that demonstrated significant differences in prognosis compared to mainstream subtypes. We assessed the immune infiltration, immunogenicity, CD8T cytotoxicity, and tumor purity of these subtypes, uncovering their distinct biological functions. Cluster 1 and Cluster 2 exhibited higher immunoreactivity, while Cluster 3 displayed higher tumor purity and poor prognosis. Gene ontology annotation and pathway analysis identified immune activation in Cluster 1, epithelial-mesenchymal transition (EMT) in Cluster 2, and cell cycle processes in Cluster 3. Notably, the impact of EMT activity on prognosis may vary across NB subtypes. A classification model using XGBoost accurately predicted subtypes in independent NB cohorts, with significant prognostic differences. GPR125, CDK4, and GREB1 emerged as potential therapeutic targets in Cluster 3. CD4K inhibitors showed subtype-specific responses, suggesting tailored treatment strategies. Single-cell analysis highlighted unfavorable clinical features in Cluster 3, including high-risk classification and reduced cytotoxicity. Suppressed interactions between monocytes, macrophages, and regulatory T cells were observed, affecting immune regulation and patient prognosis.ConclusionTo summarize, we have identified a new independent prognostic factor in NB that underscores the significant correlation between tumor phenotype and immune contexture. These findings deepen our understanding of NB subtypes and immune cell interactions, paving the way for more effective treatment approaches.

Dataset Information

Neuroblastoma Origin and Therapeutic Targets for Immunotherapy.

Publications

Neuroblastoma Origin and Therapeutic Targets for Immunotherapy.

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