Cell lineage as an indicator of immune response in neuroblastoma

细胞谱系作为神经母细胞瘤免疫反应的指标

基本信息

批准号：
10647815
负责人：
Rani E. George
金额：
$ 39.73万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-16 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10647815
关键词：
Adoptive Immunotherapy Adoptive Transfer Adrenergic Agents Affect Antibodies Antigens Biological Markers CD94 Antigen Cell Lineage Cell Therapy Cells Characteristics Childhood Extracranial Solid Tumor Childhood Solid Neoplasm Clinical Trials Design Cluster Analysis Complex Cytotoxic T-Lymphocytes Data Set Development Epigenetic Process Exhibits Gene Activation Gene Expression Profile Genes Goals Heterogeneity Immune Immune Evasion Immune Response Genes Immune response Immune system Immunologics Immunotherapy In Vitro Infiltration Inflammatory Response Licensing Ligands MYCN gene Malignant Childhood Neoplasm Malignant Neoplasms Mediating Mesenchymal Mesenchymal Cell Neoplasm Modeling Molecular Monoclonal Antibodies Mutation NK Cell Activation NK cell therapy Natural Killer Cell Immunotherapy Natural Killer Cells Neural Crest Neuroblastoma Neurons Oncogenes Patient Selection Patients Phenotype Population Primary Neoplasm Productivity Property Regimen Repression Research Proposals Resistance Role Sampling Shapes T cell infiltration T cell therapy T-Lymphocyte Testing Translating Tumor Suppression Undifferentiated Up-Regulation anti-tumor immune response cancer cell design genetic signature high risk humanized mouse immune activation immune cell infiltrate immune checkpoint blockade immunogenic immunogenicity immunoregulation improved in vivo in vivo Model innate immune sensing innovation neoplastic cell neuroblastoma cell patient stratification pre-clinical programs receptor response single-cell RNA sequencing success transcription factor treatment response treatment strategy tumor tumor growth tumor microenvironment

项目摘要

PROJECT SUMMARY/ABSTRACT The sparse landscape of targetable mutations in pediatric cancers in general and neuroblastoma (NB) in particular, together with the recent successes of the anti-GD2 antibody, dinutuximab (2), provides a compelling rationale for further development of immune-based treatment strategies against this devastating cancer. However, responses to adoptive immunotherapy and checkpoint blockade have met with limited success, partly due to an incomplete understanding of the mechanisms underlying immune responsiveness or resistance in this tumor marked by significant heterogeneity. We undertook an unbiased clustering analysis of transcriptional signatures derived from a large primary NB data set and identified a subset of tumors, characterized by the high expression of immune response activation and suppression genes, and indicating the potential for eliciting an anti-tumor immune response. These signatures were seen mainly in tumors of the mesenchymal (MES) lineage, one of the two epigenetically regulated cell states in NB, comprised of undifferentiated malignant cells with primitive neural crest-like properties. By contrast, tumors with committed, adrenergic (ADR) neuron-like malignant cells were less immunogenic and exhibited PRC2-mediated suppression of key tumor cell-intrinsic immune activation genes. These promising results led to our central hypothesis that cell lineage state is an important predictor of immune therapy response in NB. In Aim 1, we will elucidate the epigenetic mechanisms underlying lineage-specific activation of immune response genes. Aim 2 will assess lineage- dependent functions of cytotoxic T cells in tumor control by determining whether MES NB cells possess an inflamed TME that facilitates cell-based therapies. In Aim 3, we will determine whether the increased expression of NK cell receptor ligands in MES tumors translates into response to NK cell therapy and whether PRC2 inhibition will augment such responses in ADR tumors alone or in combination dinutuximab. Together, these studies are expected to provide a compelling rationale for the use of tumor cell lineage for the selection of patients who are most likely to benefit from immunotherapy and to pre-clinically validate treatment strategies involving combinations of epigenetic and immune-based therapies to target the specific immune evasion mechanisms deployed by NB cells, our long-term goal.

项目摘要/摘要小儿癌和神经母细胞瘤（NB）中可靶向突变的稀疏景观尤其是抗GD2抗体的最新成功，Dinutuximab（2）提供了令人信服的进一步开发针对这种毁灭性癌症的免疫治疗策略的理由。但是，对收养免疫疗法和检查点封锁的反应取得了有限的成功，部分是由于对此免疫反应能力或抵抗的机制不完全理解肿瘤以显着的异质性为特征。我们对转录的无偏聚类分析进行来自大型主要NB数据集的签名和确定了一部分肿瘤，其特征是免疫反应激活和抑制基因的表达，并表明引起的潜力抗肿瘤免疫反应。这些特征主要在间充质（MES）谱系的肿瘤中看到， NB中两个表观遗传调节的细胞态之一，由未分化的恶性细胞组成原始的神经rest样性质。相比之下，具有致命的肾上腺素能（ADR）神经元样的肿瘤样恶性细胞的免疫原性较少，并表现出PRC2介导的关键肿瘤细胞中性抑制免疫激活基因。这些有希望的结果导致了我们的中心假设，即细胞谱系状态是 NB中免疫治疗反应的重要预测指标。在AIM 1中，我们将阐明表观遗传免疫反应基因的谱系特异性激活的基础机制。 AIM 2将评估血统 - 通过确定MES NB细胞是否具有促进基于细胞的疗法的TME发炎。在AIM 3中，我们将确定表达是否增加 MES肿瘤中NK细胞受体配体的反应转化为对NK细胞疗法的反应以及PRC2是否抑制作用将增加单独或Dinutuximab组合中的ADR肿瘤中的这种反应。在一起，这些预计研究为使用肿瘤细胞谱系的患者选择提供了令人信服的理由。谁最有可能从免疫疗法中受益，并在链接前验证涉及的治疗策略靶向特定免疫逃避机制的表观遗传和基于免疫的疗法的组合由NB细胞部署，我们的长期目标。