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

跨学科流行病学联盟研究结直肠癌中的 T 细胞反应

基本信息

批准号：
10686351
负责人：
Shuji Ogino
金额：
$ 69.2万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686351
关键词：
Accounting Adaptive Immune System Address Alcohol consumption Area Aspirin Bacterial Genes Bacterial Toxins Bacteroides fragilis toxin CD3 Antigens CD8B1 gene Cancer Prognosis Cells Characteristics Colorectal Cancer Colorectal Neoplasms DNA sequencing Data Development Dimensions Epidemiology Evolution FOXP3 gene Fusobacterium nucleatum Genes Genetic Genetic Variation Genotype HLA Antigens Human Immune Immune response Immune system Immunofluorescence Immunologic Immunoglobulins Immunohistochemistry Immunotherapeutic agent Killer Cells Life Style Machine Learning Macrophage Mutate Obesity Observational Study Oncogenic Pathogenicity Patient-Focused Outcomes Pattern Phenotype Physical activity Prevention Prognostic Factor Proteins Ras/Raf Receptor Gene Research Resources Role Signal Pathway Signaling Protein Smoking Somatic Mutation Spatial Distribution T cell response T memory cell T-Lymphocyte T-Lymphocyte Subsets T-cell receptor repertoire Tumor Antigens Tumor Tissue Uncertainty Variant WNT Signaling Pathway Work adaptive immune response biomarker panel cancer survival cell mediated immune response cell type colon cancer family registry colon cancer patients colorectal cancer treatment combinatorial density digital imaging epidemiologic data epidemiology study follow-up genetic resource genetic variant genome-wide homeobox protein PITX1 immune function insight lifestyle factors microbial neoantigens neoplastic cell novel prognostic prognostic significance prospective response stem survival outcome tumor tumor microenvironment

项目摘要

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.

项目概要/摘要免疫系统对许多肿瘤类型的进化和进展具有关键影响，包括结直肠癌（CRC）。特别是，CRC 中存在强烈的 T 细胞反应，表明适应性免疫系统与更好的患者预后相关。因此，最近开发的免疫治疗方法通常试图利用适应性免疫反应。免疫细胞是一种肿瘤微环境的组成部分，并与肿瘤细胞动态相互作用。然而，我们对 T 细胞反应的复杂性以及驱动该反应的因素的理解仍然存在有限的。该提案的目的是确定与 T 相关的遗传、生活方式和肿瘤因素 CRC 中的细胞反应，并描述该反应对生存的影响。具体来说，在目标 1 中，我们将检查个人特征与 CRC 中 T 细胞反应的关系，包括 (1a) 的作用人类白细胞抗原 (HLA) 和杀伤细胞免疫球蛋白样受体内的种系遗传变异 (KIR) 基因，以及 (1b) 生活方式因素（例如阿司匹林使用、吸烟、饮酒）。在目标 2 中，我们将重点关注与 T 细胞反应相关的几个结直肠肿瘤特征，包括 (2a) 的存在 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途径（例如 WNT 信号传导和 RAS/RAF）。在目标 3 中，我们将评估不同方面的关联 T 细胞反应与 CRC 存活的关系，考虑了已知的预后因素和中确定的关系目标 1-2。为了实现这些目标，我们建议评估特定 T 细胞的密度和空间分布使用多重免疫荧光 (mIF) 量化表达水平和共表达模式的子集单细胞水平上的 CD3、CD4、CD8、CD45RO 和 FOXP3。这种多重评估将使我们能够检查 CRC 中 T 细胞反应的众多指标的流行病学和预后相关性。这研究将利用结直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 是一项大型协作成果 CRC 的观察性研究之间。我们已经完成了全基因组种系基因分型，并已关于所有人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基因进行 DNA 测序。 CRC肿瘤组织中细菌基因的数量。生存的前瞻性随访正在进行中，我们已经协调现有的生存数据。通过这个项目，我们将在 CRC 中添加有关 T 细胞反应的信息 GECCO-CCFR 资源中有超过 2,500 个 CRC 案例。该项目提供了前所未有的机会研究 CRC 中 T 细胞反应的流行病学以及该反应与个人的关系和肿瘤特征。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以及有针对性地实施新兴免疫治疗和免疫预防策略。