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

 描述(申请人提供)：经典型霍奇金淋巴瘤(CHL)是西方世界30岁以下人群中最常见的淋巴瘤。在年轻人中，最初治疗后的治疗反应很好，但迟发效应会导致相当大的死亡率和发病率。25%-30%的患者在最初的治疗后复发或进展，5%-15%的患者在10年内死于他们的疾病。提高对慢性淋巴细胞白血病的病理生物学的了解是开发生物标记物和新的治疗方法以改善初始和晚期结果的基本要求。CHL在癌症中是独一无二的，因为恶性细胞占肿瘤的比例不到1%，其余的肿瘤微环境(TME)由各种免疫细胞组成。我们已经证明，在某些人群中，TME的组成会影响CHL的结果。在这里，我们将研究TME成分与慢性粒细胞白血病存活率、年龄、性别、EB病毒状态、组织学和种族/民族之间的相关性(目标1)。我们还将研究宿主因素(年龄、性别、种族/民族、社会经济地位)、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是否调节或与宿主因素相互作用影响生存(目标3)。这将是迄今为止对CHL TME进行的最大规模的研究，也是唯一一项专门研究不同种族/民族和年龄组之间的关系的研究。为了进行这项研究，我们组建了一个多学科的专家团队。我们将使用纳米串进行基因表达谱分析(我们经过验证的Scott预测器)，并将使用来自5个大型临床中心的2688名美国多民族慢性粒细胞白血病患者的福尔马林固定石蜡包埋诊断活检的免疫组织化学方法，检测特定的T细胞和其他亚群，包括巨噬细胞和B细胞。肿瘤细胞中的EBV DNA也将被测量。组织微阵列将被构建，免疫组织化学将自动评分。我们还将收集人口统计和临床数据，包括年龄、种族/民族、性别、社会经济地位、治疗、无进展和总体生存率、B症状、解剖部位、分期和其他信息。在此样本量下，对于频率从0.1到0.5的TME二元变量，80%功率的最小可检测危险比(HR)分别为1.55到1.32。可检测到的边际人力资源的范围在以前观察到的影响范围内，应该使我们能够测试种族/族裔、年龄和其他因素的边际影响。这项建议的意义在于确定一个尖端临床生物标记物的人群差异，并阐明不同人群中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.