Identifying therapeutic pathways targeting medulloblastoma-immune cell interactions

摘要 我们建议发展一种系统生物学的方法来理解肿瘤和免疫之间的相互作用。 细胞及其临床意义。我们的工作将集中在髓母细胞瘤，一种儿童恶性脑瘤 我们的团队在这方面有丰富的专业知识。我们和其他人已经证明，髓母细胞瘤是 尽管有血脑屏障，但免疫活性下降。然而，这些免疫细胞的临床后果 都是不清楚的，而且几乎没有信息可以指导调节这些的治疗方法的发展 免疫细胞。 我们的创新策略结合了单细胞方法，包括单细胞蛋白质组学，以及复杂的 计算分析。在目标1中，我们使用测序和 人体样本的成像方法。目标2建立了一个支配分子相互作用的因果模型 髓母细胞瘤中细胞类型之间的相互作用决定了这些细胞的临床相关性，以及 确定潜在的治疗目标。AIM 3绘制了经过良好验证的小鼠的肿瘤免疫环境图 这种疾病的模型，并为小鼠建立与人类平行的计算模型。假设 来自Aim 2的可能很好地翻译到小鼠模型上的基因随后被测试它们对肿瘤的影响 成长和生存。鼠标结果用于更新计算模型并优化 治疗策略。我们预计，这一项目的成功完成将对 髓母细胞瘤治疗学。此外，我们开发的方法将促进对 免疫细胞和髓母细胞瘤以外的许多其他类型的肿瘤。

SUMMARY We propose developing a systems-biology approach to understand interactions between tumor and immune cells and their clinical implications. Our work will focus on medulloblastoma, a malignant pediatric brain tumor in which our team has extensive expertise. We and others have shown that medulloblastoma tumors are sites of immune activity despite the blood-brain barrier. However, the clinical consequences of these immune cells are unclear and there is little information that might guide development of therapeutics that modulate these immune cells. Our innovative strategy combines single-cell methods, including single-cell proteomics, with a sophisticated computational analysis. In Aim 1, we map the landscape of tumor-immune interactions using sequencing and imaging methods on human samples. Aim 2 builds a causal model of the molecular interactions that govern interactions among cell types in medulloblastoma, determines the clinical correlates of these cells, and identifies potential therapeutic targets. Aim 3 maps the tumor-immune environment in well-validated mouse models of the disease, and builds computational models for mice parallel to those for humans. Hypotheses from Aim 2 that are likely to translate well to the mouse models are then tested for their effects on tumor growth and survival. The mouse results are used to update the computational models and refine the therapeutic strategies. We expect that successful completion of this project will have a substantial impact on medulloblastoma therapeutics. Further, the methods we develop will catalyze research of interactions between immune cells and many other tumor types beyond medulloblastoma.