Host factors, tumor microenvironment and survival in a multiethnic study of Hodgkin lymphoma patients

 描述（由申请人提供）：经典霍奇金淋巴瘤（cHL）是西方世界30岁以下人群中最常见的淋巴瘤。初始治疗后的治疗反应在年轻人中是极好的，但是晚期效应导致相当大的死亡率和发病率。25-30%的患者在初始治疗后经历复发或疾病进展，5-15%的患者在10年内死于疾病。更好地理解cHL的病理生物学是生物标志物开发和改善初始和晚期结局的新治疗方法的基本要求。cHL在癌症中是独特的，因为恶性细胞占肿瘤的不到1%，肿瘤微环境（TME）的其余部分由各种免疫细胞组成。我们已经证明，在某些人群中，TME的组成影响cHL的结果。在这里，我们将检查TME组成与cHL生存率之间的相关性，包括年龄、性别、EBV状态、组织学和种族/民族（目标1）。我们还将检查宿主因素（年龄、性别、种族/民族、SES）、EBV状态和组织学对TME组成的影响（目标2），我们将进行分析以确定TME是否介导或与宿主因素相互作用以影响生存率（目标3）。这将是迄今为止进行的最大规模的cHL TME研究，也是唯一一项专门研究不同种族/民族和年龄组之间关系的研究。为了进行这项研究，我们组建了一个多学科专家团队。我们将使用NanoString进行基因表达谱分析（我们经过验证的Scott Predictor），并将使用来自5个大型临床中心的2，688名美国多种族cHL患者的福尔马林固定石蜡包埋诊断活检的免疫组织化学检查与结果有关的特定T细胞和其他亚群，包括巨噬细胞和B细胞。还将测量肿瘤细胞中的EBV DNA。将构建组织微阵列，并自动进行免疫组织化学评分。我们还将收集人口统计学和临床数据，包括年龄、人种/种族、性别、社会经济地位、治疗、无进展生存期和总生存期、B症状、解剖部位、分期和其他信息。在该样本量下，对于频率范围为0.1 - 0.5的TME二元变量，80%把握度下的最小可检测风险比（HR）分别为1.55 - 1.32。可检测的边际HR范围完全在先前观察到的效应范围内，应使我们能够通过人种/种族、年龄和其他因素检测边际效应。该建议的意义在于确定尖端临床生物标志物的人群差异，并阐明不同人口统计学群体中TME的免疫生物学。

 DESCRIPTION (provided by applicant): Classical Hodgkin lymphoma (cHL) is the most common form of lymphoma affecting people under the age of 30 in the Western World. Treatment responses after initial therapies are excellent in young people, however late effects cause considerable mortality and morbidity. 25- 30% of patients experience relapse or progressive disease following initial treatment and 5-15% die of their disease within 10 years. An improved understanding of the pathobiology of cHL is an essential requirement for biomarker development and novel therapeutic approaches to improve initial and late outcomes. cHL is unique among cancers in that the malignant cells comprise less than 1% of the tumor with the remainder of the tumor microenvironment (TME) composed of a variety of immune cells. We have shown that in some populations, the composition of the TME affects cHL outcome. Here we will examine the correlation between the TME composition and survival in cHL across, age, sex, EBV status, histology and racial/ethnic groups (Aim 1). We will also examine the effect of host factors (age, sex, race/ethnicity, SES), EBV status and histology on TME composition (Aim 2) and we will conduct analyses to determine whether TME mediates or interacts with host factors to impact survival (Aim 3). This will be the largest study of cHL TME conducted to date and the only one designed to specifically examine relationships in different racial/ethnic and age groups. To conduct this study, we have assembled a multidisciplinary team of experts. We will perform gene expression profiling (our validated Scott Predictor) using NanoString and we will examine specific T-cell and other subsets, including macrophages and B-cells, implicated in outcome, using immunohistochemistry on formalin-fixed paraffin-embedded diagnostic biopsies from 2,688 U.S. multiethnic cHL patients from 5 large clinical centers. EBV DNA in the tumor cells will also be measured. Tissue microarrays will be constructed and immunohistochemistry automatically scored. We will also collect demographic and clinical data including age, race/ethnicity, sex, socioeconomic status, treatment, progression-free and overall survival, B symptoms, anatomic site, stage and other information. With this sample size, the minimum detectable Hazard Ratio (HR) with 80% power is 1.55 to 1.32 for a TME binary variable with frequency ranging from 0.1 to 0.5, respectively. The ranges of detectable marginal HR are well-within the range of previously observed effects and should enable us to test marginal effects by race/ethnicity, age and other factors. The significance of this proposal lies in identifying population differences for a cutting-edge clinical biomarker and elucidating the immunobiology of the TME in different demographic groups.