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

• 批准号: 10467445
• 负责人: Rani E. George
• 金额: $ 40.54万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 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/10467445
• 关键词: Address; 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 Cells; Neural Crest; Neuroblastoma; Neurons; Oncogenes; Patient Selection; Patients; Phenotype; Population; Primary Neoplasm; Property; Regimen; Repression; Research Proposals; Resistance; Role; Sampling; Shapes; T cell therapy; T-Lymphocyte; Testing; Translating; Tumor Suppression; Tumor-infiltrating immune cells; Undifferentiated; Up-Regulation; anti-tumor immune response; cancer cell; design; epigenetic silencing; genetic signature; high risk; humanized mouse; immune activation; immune checkpoint blockade; immunogenic; immunogenicity; immunoregulation; improved; in vivo; in vivo Model; innate immune sensing; innovation; neoplastic cell; neuroblastoma cell; patient stratification; pre-clinical; receptor; response; single-cell RNA sequencing; success; transcription factor; treatment response; treatment strategy; tumor; tumor growth; tumor microenvironment

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.

项目概要/摘要 一般儿科癌症和神经母细胞瘤 (NB) 中的靶向突变情况稀疏 特别是，再加上抗 GD2 抗体 dinutuximab (2) 最近取得的成功，提供了令人信服的证据 进一步开发针对这种毁灭性癌症的基于免疫的治疗策略的基本原理。 然而，对过继免疫疗法和检查点封锁的反应取得了有限的成功，部分原因是 由于对免疫反应或抵抗的机制不完全了解 肿瘤具有显着的异质性。我们对转录进行了无偏聚类分析 来自大型主NB数据集的签名以及 确定了肿瘤的一个子集，其特征是高 免疫反应激活和抑制基因的表达，并表明引发免疫反应的潜力 抗肿瘤免疫反应。这些特征主要见于间充质（MES）谱系的肿瘤， NB 中两种表观遗传调节细胞状态之一，由未分化的恶性细胞组成 原始神经嵴样特性。相比之下，具有定向肾上腺素能 (ADR) 神经元样的肿瘤 恶性细胞的免疫原性较低，并表现出 PRC2 介导的关键肿瘤细胞内在抑制 免疫激活基因。这些有希望的结果引出了我们的中心假设：细胞谱系状态是一个 NB 免疫治疗反应的重要预测因子。在目标 1 中，我们将阐明表观遗传 免疫反应基因谱系特异性激活的机制。目标 2 将评估血统 - 通过确定 MES NB 细胞是否具有细胞毒性 T 细胞在肿瘤控制中的依赖性功能 发炎的 TME，促进基于细胞的治疗。在目标 3 中，我们将确定增加的表达是否 MES 肿瘤中 NK 细胞受体配体的变化转化为对 NK 细胞治疗的反应以及 PRC2 是否 单独或联合 dinutuximab 抑制将增强 ADR 肿瘤中的此类反应。在一起，这些 预计研究将为使用肿瘤细胞谱系选择患者提供令人信服的理由 谁最有可能从免疫疗法中受益并进行临床前验证治疗策略，包括 表观遗传学和免疫疗法相结合，针对特定的免疫逃避机制 NB小区部署，是我们的长期目标。