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Defining the mechanisms of B7-H3 overexpression and role in neuroblastoma metastasis and immune evasion

定义 B7-H3 过度表达的机制及其在神经母细胞瘤转移和免疫逃避中的作用

基本信息

批准号：
10750399
负责人：
Catherine Leona-Grace Wingrove
金额：
$ 4.77万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750399
关键词：
3-Dimensional Adrenergic Agents Adult Antibody-drug conjugates Antigens Automobile Driving Binding Biological Assay Biological Process C57BL/6 Mouse CD276 gene CD3 Antigens CRISPR/Cas technology Cell Line Cell Proliferation Cell Surface Proteins Cell physiology Cell secretion ChIP-seq Characteristics Chemotherapy-Oncologic Procedure Childhood Childhood Extracranial Solid Tumor Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Credentialing Cytolysis Data Dependence Development Diagnosis Effector Cell Event FDA approved Family Fiber Future Genes Genetic Genetic Transcription Growth Human Human Cell Line Immune Immune Evasion Immunocompetent Immunologic Deficiency Syndromes Immunophenotyping Immunotherapeutic agent Immunotherapy In Vitro Inflammatory Integral Membrane Protein Interferons Interleukin-2 International Invaded Life Ligands Luciferases MART-1 Tumor Antigen MYCN gene Malignant Childhood Neoplasm Malignant Neoplasms Mediating Mediator Mesenchymal Migration Assay Monoclonal Antibody Therapy Morbidity - disease rate Mutate Mutation National Research Service Awards Natural Killer Cell Immunotherapy Natural Killer Cells Neoplasm Metastasis Neuroblastoma Oncogenes Oncogenic Oncoproteins Operative Surgical Procedures Pain Pathway interactions Patient-Focused Outcomes Patients Proliferating Proteins Proto-Oncogene Proteins c-myc Public Health Radiation Recombinants Research Resistance Role Scientist Seminal Solid Solid Neoplasm Survival Rate Survivors Sympathetic Nervous System System T cell response T-Cell Activation T-Lymphocyte TNF gene Testing Toxic effect Transforming Growth Factor beta Transgenic Organisms Translational Research Treatment Protocols Tumor Antigens Work Xenograft procedure antigen-specific T cells career cell growth chemoradiation chimeric antigen receptor T cells clinically relevant comorbidity cytokine cytotoxicity differential expression disorder risk evidence base high risk immunoregulation improved improved outcome in vivo inhibitor knock-down migration mortality mouse model neuroblastoma cell new therapeutic target novel novel therapeutics overexpression pharmacologic pre-clinical promoter research clinical testing response side effect skills success targeted treatment therapeutic target transcription factor treatment strategy tumor tumor growth tumor microenvironment wound

项目摘要

Project Summary Neuroblastoma is a cancer derived from the developing sympathetic nervous system and is the most commonly diagnosed extracranial solid tumor of childhood. Despite an intensive treatment regimen of chemotherapy, surgery, radiation, and immunotherapy, the five-year survival rate of high-risk neuroblastoma patients remains at only 50%. The low tumor mutational burden of neuroblastoma has challenged the development of targeted- and immuno-therapies, however moderate success has been achieved by targeting GD2 with monoclonal antibody therapy, credentialing immunotherapeutic treatment strategies for neuroblastoma as a promising approach. The success of GD2-targeted therapy to date has been hindered due to debilitating side effects from on-target/off-tumor toxicity since GD2 is also expressed on pain fibers, and antigen loss as a mechanism of therapy resistance. Therefore, there is an unmet need for the discovery of new therapeutic targets in neuroblastoma. B7-H3, encoded by the CD276 gene, is a type 1 transmembrane protein in the B7 family of immunoregulatory proteins and is highly expressed in many adult and pediatric cancers, including neuroblastoma. In addition to being implicated in immunoinhibition, B7-H3 may also mediate tumor migration and metastasis. Preclinical success of several immunotherapeutic strategies directed toward B7-H3, including CAR-T cells and antibody drug conjugates, suggest that B7-H3 is a targetable tumor-associated antigen with several pediatric clinical trials ongoing or planned. Therefore, it is critical to understand the oncogenic functions of B7-H3 and how its expression is regulated to anticipate mechanisms of therapy resistance. Our central hypothesis is that B7-H3 promotes neuroblastoma metastasis and immune evasion, and its expression is regulated by tumor microenvironment-derived cytokines and neuroblastoma-specific transcription factors. Our preliminary data shows that B7-H3 knockdown using CRISPRi in neuroblastoma cell lines inhibits cellular proliferation. Additionally, ChIP-sequencing data identifies regions of MYC and MYCN binding at the B7-H3 promoter indicating a potential role of the MYC transcription factors in regulating B7-H3 expression. B7-H3 expression may also be regulated by inflammatory cytokines, as neuroblastoma cell lines upregulate B7-H3 expression following TNF-α or TGF-β exposure. Finally, recombinant human B7-H3 inhibits T cell activation, TNF-α, and IFN-y. Uncovering how B7-H3 promotes immune evasion in neuroblastoma is crucial given the T and NK cell-based immunotherapies undergoing clinical testing. We propose that B7-H3 is a multifunctional protein that serves as a promising therapeutic target in neuroblastoma. This NRSA F31 will define the mechanisms of neuroblastoma dependance on B7-H3 for metastasis and immune evasion, while also defining mechanisms of overexpression, to inform future B7-H3-targeting therapies and ultimately improve outcomes for patients with high-risk neuroblastoma.

项目总结