DNA-based Immune Phenotyping in HNSCC for Biomarkers of Response to Immunotherapy

项目摘要/摘要 头颈部鳞状细胞癌(HNSCCs)是一种破坏性的上呼吸道肿瘤，与 免疫抑制网络影响肿瘤微环境、骨髓和外周 血液隔间。癌症免疫的新生物标志物的发展还没有跟上 我们对癌症相关炎症及其与异常的关系的认识取得突破 造血和免疫抑制白细胞群体的产生。生物标志物也没有跟上步伐 具有免疫调节治疗的临床适应症。在这里，我们解决了临床适用的差距 通过首次开发独特的免疫甲基化工具来识别异常的外周免疫的免疫生物标记物 细胞群，然后应用这些工具来研究HNSCC的存活率。美国食品和药物管理局最近 批准的Pembrolizumab联合或不联合化疗作为转移性或不可切除的一线治疗 复发性疾病，这将极大地增加接受免疫治疗的患者数量 HNSCC，进一步强调了识别治疗反应的生物标记物的迫切需要，甚至在De之前 药品成本的事实问题。此外，最近成功的免疫调节剂治疗晚期试验 HNSCC揭示，免疫系统在疾病生存和预后中起着至关重要的作用。至 了解和量化免疫状态，我们建议应用新的基于DNA甲基化的免疫 表型生物标记物将定义免疫抑制状态，并允许我们深入研究其 HNSCC免疫治疗反应的关系。拟议的研究将借鉴两项 NCI指定的综合癌症中心独立的、可比较的、前瞻性收集的患者队列 中锋。在癌症患者体内追踪细胞克隆的单细胞追踪方法的结果显示 引人注目的证据表明，固有的吸引新免疫细胞到肿瘤的能力导致了检查点的改善 封锁活动。这一发现有力地支持了我们识别检查点封锁的生物标志物的方法 通过测量外周血中的含量来做出反应。随着针对HNSCC的新免疫疗法的开发， 对调节宿主免疫系统受损的影响至关重要。新一代表观遗传学 免疫分析技术将提供生物标记物，在评估免疫状态和在 阐述免疫调节剂的作用机制。

PROJECT SUMMARY/ABSTRACT Head and Neck Squamous Cell Carcinomas (HNSCCs) are devastating upper airway tumors that are associated with an immunosuppressive network impacting the tumor microenvironment, bone marrow and the peripheral blood compartments. The development of novel biomarkers 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 immunosuppressive leukocyte populations. Nor have biomarkers kept pace with clinical indications for use of immunomodulatory therapies. Here, we address the gap in clinically applicable immune biomarkers by first developing unique immuno-methylomic tools to identify aberrant peripheral immune cell populations, followed by the application of such tools for studying HNSCC survivorship. The FDA recently approved pembrolizumab with or without chemotherapy as a first-line treatment for metastatic, or unresectable recurrent disease, which is poised to dramatically increase the number of patients receiving immunotherapy for HNSCC, further underscoring the critical need to identify biomarkers of response to treatment, even before de facto issues of drug cost. Further, recent successful trials of immunomodulatory agents treating late stage HNSCC reveal that there is a crucial role for the immune system in disease survival and prognosis. To understand and quantify immune status, we propose to apply novel DNA methylation-based immune phenotyping biomarkers that will define the immune suppressive state and allow us to intensively study its relationship to immunotherapy treatment response in HNSCC. The proposed study will draw from two independent, comparable, prospectively collected patient cohorts at NCI-designated Comprehensive Cancer Centers. Results from single cell tracing approaches to follow clones of cells in-vivo in cancer patients showed dramatic evidence that the intrinsic ability to attract new immune cells to the tumor results in improved checkpoint blockade activity. This finding strongly supports our approach to identifying biomarkers of checkpoint blockade response through measures in the peripheral blood. As new immunotherapies are developed for HNSCC, it is crucial to mediate the effects of the host’s compromised immune system. The new generation of epigenetic techniques for immune profiling will provide biomarkers that are useful both in assessing immune status and in addressing mechanisms of immune modifiers.