(PQ3) Immune epigenetic biomarkers of bladder cancer outcomes

摘要 估计有765，000人诊断膀胱癌生活在美国和风险 疾病复发和进展的概率可能很高。频繁的侵入性经尿道筛查程序， 监测复发和进展给患者和医疗保健系统带来负担。更好的 了解膀胱癌患者的肿瘤相关免疫反应可以提供更多 关于侵入性随访程序的必要频率的知情临床决策，并减少患者 发病率我们建议利用现有的基于人群的膀胱癌研究，包括一系列 患者年龄组，有几年的随访，包括患者治疗和结局数据，以及 匹配的肿瘤样本我们的合作小组已经开发并广泛验证了表观遗传 白细胞亚型的生物标志物，允许使用档案DNA研究免疫概况。在这里，我们将使用 我们已证实的框架，以扩大我们的白细胞表观遗传生物标志物的库，包括髓源性 抑制细胞（MDSC），并测试和验证MDSC与其他白细胞亚型（包括 中性粒细胞与淋巴细胞比率（NLR）和细胞类型活化状态与膀胱癌结果; 复发、进展和生存。我们将使用时间到事件分析，并旨在了解 免疫特征、诊断时年龄、肿瘤分期和分级、吸烟史的独立贡献，以及 治疗（包括BCG免疫疗法），与膀胱癌的结果。此外，我们建议， 匹配受试者膀胱肿瘤的体细胞改变谱，并评估血液免疫 肿瘤甲基化和存活率的特征，以了解肿瘤特征和患者之间的串扰 免疫反应。最后，在一个探索性的目标，我们将前瞻性地研究治疗前和治疗后， 膀胱癌患者的治疗免疫特征。在这个新兴的适当时机 免疫调节疗法我们现有的基于人群的研究资源提供了一个具有成本效益的环境 通过引入一种新颖灵活的方法， 免疫监测工具包，可以使用肿瘤相关免疫数据为临床决策提供信息 应答

ABSTRACT There are an estimated 765,000 people with a diagnosis of bladder cancer living in the United States and risk of disease recurrence and progression can be high. Frequent, invasive transurethral screening procedures to monitor for recurrence and progression burden both patients and the health care system. A better understanding of the tumor-associated immune responses in bladder cancer patients could provide for more informed clinical decisions on the necessary frequency of invasive follow up procedures and reduce patient morbidity. We propose to leverage an existing population-based study of bladder cancer that includes a range of patient age groups, has several years of follow up, includes patient treatment and outcome data, as well as matched tumor samples. Our collaborative group has developed and extensively validated epigenetic biomarkers of leukocyte subtypes allowing the use of archival DNA to study immune profiles. Here we will use our proven framework to expand our repertoire of leukocyte epigenetic biomarkers to include myeloid derived suppressor cells (MDSC), and test and validate the relation of MDSC and other leukocyte subtypes (including the neutrophil to lymphocyte ratio: NLR), and cell type activation states with bladder cancer outcomes; recurrence, progression, and survival. We will use time-to-event analysis and aim to understand the independent contributions of immune profiles, age at diagnosis, tumor stage and grade, smoking history, and treatment (including BCG immunotherapy), with bladder cancer outcomes. In addition, we propose to measure somatic alteration profiles of bladder tumors from matched subjects and assess the relation of blood immune signatures with tumor methylation and survival to understand the crosstalk between tumor profiles and patient immune responses. Finally, in an exploratory aim we will prospectively investigate both pre-treatment and post- treatment immune signatures in bladder cancer patients. At this opportune time of emerging immunomodulatory therapeutics our existing population-based study resource provides a cost-efficient setting to advance towards improved risk projection in newly diagnosed patients by ushering in a novel and flexible immune monitoring toolkit that can inform clinical decision-making using data on tumor-associated immune responses.