Interdisciplinary Epidemiologic Consortium to Investigate T-cell Response in Colorectal Cancer

项目概要/摘要 免疫系统在许多肿瘤类型的演变和发展中具有关键影响，包括 结直肠癌（CRC）。特别地，在CRC中存在强烈的T细胞应答，表明CRC的活化。 适应性免疫系统，与更好的患者结果有关。因此，最近开发的 免疫学方法通常试图利用适应性免疫应答。免疫细胞是 肿瘤微环境的组成部分，并动态地与肿瘤细胞相互作用。然而，在这方面， 我们对T细胞反应的复杂性和驱动这种反应的因素的理解仍然是 有限公司这项建议的目的是确定与T细胞相关的遗传、生活方式和肿瘤因素。 CRC中的细胞反应，并表征该反应的生存影响。具体而言，在目标1中， 将研究个人特征与CRC中T细胞反应的关系，包括（1a） 人类白细胞抗原（HLA）和巨噬细胞免疫球蛋白样受体内的生殖系遗传变异 (KIR)基因，和（1b）生活方式因素（例如，阿司匹林使用、吸烟、饮酒）。在目标2中，我们将专注于 对与T细胞应答相关的几种结肠直肠肿瘤特征的影响，包括（2a） CRC中的具核梭杆菌和细菌毒素基因，以及（2b）关键信号传导中的体细胞突变 路径（例如，WNT信号和RAS/RAF）。在目标3中，我们将评估不同方面的关联 T细胞应答与CRC生存率的关系，解释了已知的预后因素和 目标1-2。为了实现这些目标，我们建议评估特异性T细胞的密度和空间分布， 使用多重免疫荧光（mIF）来量化表达水平和共表达模式的子集 CD 3、CD 4、CD 8、CD 45 RO和FOXP 3在单细胞水平的表达。这种多重评估将使我们能够 检查CRC中T细胞应答的众多指标的流行病学和预后相关性。这 研究将利用大肠癌遗传学和流行病学联盟的资源 （GECCO）和结肠癌家族登记处（CCFR）。GECCO-CCFR是一个大型的合作项目， CRC的观察性研究之间。我们已经完成了全基因组生殖系基因分型， 关于所有人的各种生活方式因素和个人特征的统一流行病学数据 参与研究。我们正在对一组205个人类基因和一个小的 CRC肿瘤组织中细菌基因的数量。生存期的前瞻性随访正在进行中，我们有 协调现有的生存数据。通过这个项目，我们将增加CRC中T细胞应答的信息， 向GECCO-CCFR资源提供2，500多个CRC病例。该项目提供了前所未有的机会， 调查CRC中T细胞反应的流行病学以及该反应与个人 和肿瘤特征。通过这项新颖的研究获得的见解最终可以为发展提供信息 并有针对性地实施新兴的免疫和免疫预防战略。

PROJECT SUMMARY / ABSTRACT The immune system has pivotal influence in the evolution and progression of many tumor types, including colorectal cancer (CRC). In particular, the presence of a strong T cell response in CRC, indicating activation of the adaptive immune system, has been associated with better patient outcomes. As such, recently developed immunotherapeutic approaches often attempt to harness the adaptive immune response. Immune cells are an integral component of the tumor microenvironment, and dynamically interact with neoplastic cells. However, our understanding as to the complexity of the T cell response and the factors that drive this response remains limited. The objective of this proposal is to identify genetic, lifestyle, and tumor factors associated with the T cell response in CRC, and to characterize the survival implications of that response. Specifically, in Aim 1 we will examine the relationship of personal characteristics with T cell response in CRC, including the role of (1a) germline genetic variation within human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptor (KIR) genes, and (1b) lifestyle factors (e.g., aspirin use, smoking, alcohol consumption). In Aim 2 we will focus on several colorectal tumor characteristics as they relate to T cell response, including (2a) the presence of Fusobacterium nucleatum and bacterial toxin genes in CRC, and (2b) somatic mutations in key signaling pathways (e.g., WNT signaling and RAS/RAF). In Aim 3, we will evaluate the associations of different aspects of T cell response with CRC survival, accounting for known prognostic factors and the relationships identified in Aims 1-2. To achieve these Aims, we propose to assess the density and spatial distribution of specific T cell subsets using multiplexed immunofluorescence (mIF) to quantify expression levels and co-expression patterns of CD3, CD4, CD8, CD45RO, and FOXP3 at the single cell level. This multiplexed assessment will allow us to examine the epidemiologic and prognostic relevance of numerous metrics of T cell response in CRC. This research will leverage the resources of the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and the Colon Cancer Family Registry (CCFR). GECCO-CCFR is a large collaborative effort between observational studies of CRC. We have completed genome-wide germline genotyping and have harmonized epidemiologic data regarding a variety of lifestyle factors and personal characteristics for all participating studies. We are conducting DNA sequencing with a panel of 205 human genes and a small number of bacterial genes in CRC tumor tissue. Prospective follow-up for survival is ongoing, and we have harmonized existing survival data. Through this project, we will add information on T cell response in CRC for >2,500 CRC cases to the GECCO-CCFR resource. This project provides an unprecedented opportunity to investigate the epidemiology of the T cell response in CRC and the relationship of that response with personal and tumor characteristics. Insights gained through this novel study could ultimately inform the development and targeted implementation of emerging immunotherapeutic and immunopreventative strategies.