Project 1: Blood Immunomethylomic Markers of Outcome in Glioblastoma Patients

项目总结/摘要 胶质母细胞瘤（GBM）是一种破坏性的中枢神经系统肿瘤，与神经系统肿瘤相关。 影响肿瘤微环境、骨髓和外周血的免疫抑制网络 隔间癌症免疫的新标志物的发展没有跟上突破的步伐 在我们对癌症相关炎症及其与异常造血的关系的理解中， 髓源性抑制细胞的产生。我们认识上的这一差距是一个公认的高度优先事项 癌症免疫治疗的新时代癌症登月蓝丝带小组建议作为一个关键 可行的目标“，以开发克服阻塞性，免疫抑制性肿瘤环境的方法 儿童和成人”。我们的项目通过开发和测试一个高度 测量GBM患者免疫抑制的创新方法。我们强大的免疫方法 基于独特的免疫细胞DNA甲基化指纹的分析更具有可重复性， 比当前的方法更具侵入性且成本高昂。使用这种新的免疫甲基化方法进行免疫分析 在目标1中，我们将连续评估一大组新诊断GBM患者的免疫状态， 通过手术、放疗和化疗进行初步诊断。在5个时间点中的每一个， 将评估每个患者的免疫抑制性髓源性抑制细胞和其他细胞类型的水平 通过外周血免疫谱。确定治疗反应和肿瘤的临床相关性 我们还将评估每个患者的MRI扫描结果。在目标2中，我们将评估 甲基化产生的免疫谱（髓源性抑制细胞、CD 4、CD 8、T- 细胞、B细胞、NK、单核细胞和嗜中性粒细胞）和其他因素在GBM患者存活和进展中的作用。在 目的3我们将评估患者免疫谱的新信息如何影响临床决策 制作。我们将建立全面的统计模型，包括相关的临床变量，以预测患者 生存和肿瘤进展以及包括免疫因素和临床 变量严格比较纯临床与组合模型（包括免疫因素）， 将进行评估，并将揭示免疫概况如何改善GBM结果预测。的最终结果 这些研究将使临床医生和患者更好地了解他们的预后， 用于未来临床试验的分层。改善对肿瘤进展的预测将有助于避免不必要的 可能具有侵入性和潜在危害的干预措施。结合基于DNA的免疫评估 GBM生存和进展的预后模型中的因素将为患者的治疗提供重大进展， 管理和成果。

Project Summary/Abstract Glioblastomas (GBM) are devastating central nervous system tumors that are associated with an immunosuppressive network impacting the tumor microenvironment, bone marrow and peripheral blood compartments. The development of novel markers of cancer immunity have not kept pace with breakthroughs in our understanding of cancer-associated inflammation and its relationship with abnormal hematopoiesis and the production of myeloid derived suppressor cells. This gap in our understanding is a recognized high priority in the new era of cancer immunotherapy. The Cancer Moonshot blue ribbon panel recommended as a key actionable goal “to develop approaches to overcome an obstructive, immune-suppressive tumor environment in both children and adults”. Our project addresses this important goal by developing and testing a highly innovative approach for measuring immunosuppression in GBM patients. Our powerful method for immune profiling that is based on unique immune cell DNA methylation fingerprints is more reproducible, and less intrusive and costly than current methods. Using this novel immunomethylomic approach for immune profiling in Aim 1 we will serially assess immune status in a large group of patients with newly diagnosed GBM from their initial diagnosis through their surgery, radiation and chemotherapy treatments. At each of 5 time points we will assess each patient's levels of immunosuppressive myeloid derived suppressor and other cell types through the peripheral blood immune profile. To identify clinical correlates of treatment response and tumor recurrence at each point we will also assess each patient's MRI scans. In Aim 2 we will then assess the prognostic value of methylation generated immune profiles (myeloid derived suppressor cells, CD4, CD8, T- cells, B-cells, NK, monocytes, and neutrophils) and other factors in GBM patient survival and progression. In Aim 3 we will evaluate how the new information on patient immune profiles can influence clinical decision making. We will build comprehensive statistical models that include relevant clinical variables to predict patient survival and tumor progression as well as combined models that include both immune factors and clinical variables. Rigorous comparisons of purely clinical versus combined models (which include immune factors) will be evaluated and will reveal how immune profiles can improve GBM outcome prediction. The end result of these studies will enable clinicians and patients to better understand their prognosis and improve risk stratification for future clinical trials. Improved predictions of tumor progression will help to avoid unnecessary interventions that may be invasive and potentially harmful. Incorporation of DNA based assessment of immune factors in prognostic models of GBM survival and progression will provide a major advance in patient management and outcomes.