Cell lineage as an indicator of immune response in neuroblastoma

项目总结/摘要 儿童癌症和神经母细胞瘤（NB）中靶向突变的稀疏景观， 特别是，连同抗GD 2抗体dinutuximab（2）的最近成功，提供了一个令人信服的 这是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理由。 然而，对过继性免疫治疗和检查点阻断的反应取得了有限的成功，部分原因是， 由于对免疫应答或抵抗的机制的不完全理解， 以显著的异质性为特征的肿瘤。我们进行了一个无偏的聚类分析， 从大的主NB数据集导出的签名，以及 确定了一个肿瘤子集，其特征是高 免疫应答激活和抑制基因的表达，并表明诱导免疫应答的可能性。 抗肿瘤免疫应答。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， 原始的神经嵴状特征相比之下，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PRC 2介导的抑制关键肿瘤细胞内在的 免疫激活基因这些有希望的结果导致了我们的核心假设，即细胞谱系状态是一个 NB中免疫治疗应答的重要预测因子。在目标1中，我们将阐明表观遗传 免疫应答基因的谱系特异性激活的潜在机制。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细胞受体配体的表达转化为对NK细胞治疗的应答， 抑制作用将增强单独或与地奴妥昔单抗组合的ADR肿瘤中的这种应答。所有这些 预期研究将为使用肿瘤细胞谱系来选择患者提供令人信服的理由 最有可能从免疫治疗中受益并在临床前验证治疗策略的患者， 表观遗传学和基于免疫的疗法的组合，以靶向特定的免疫逃避机制 这是我们的长期目标。

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.