The Epidemiology of Immune Responses in Colorectal Cancer

 描述（由申请人提供）：免疫系统在调节结直肠癌（CRC）的发生和进展中起关键作用，T淋巴细胞的肿瘤浸润是CRC结局的高度信息性预后因素。在过去的十年中，筛查和治疗方面的进步大大提高了CRC的生存率，但在同一TNM分期诊断的肿瘤患者中，临床结局仍然存在很大差异，20-30%的局部癌症患者会发生疾病复发。这表明，传统的预后因素，包括阶段和肿瘤浸润淋巴细胞（TIL）定量 通过光学显微镜下的专家病理学检查的经典手段，缺乏足够的粒度来预测患者结果并指导许多患者的最佳治疗选择。TIL可以通过识别HLA分子背景下呈递的异常表达抗原的增强表达来触发癌细胞的优先裂解，但是在肿瘤微环境中调节这种适应性免疫应答的宿主和肿瘤因子在很大程度上仍未被探索。我们建议通过研究现有的基于人群的4,000例结直肠癌病例的流行病学研究中调节免疫应答的因素来解决这些知识空白，这些病例具有基本上完美的临床注释和随访。现在，一项新的技术进步允许直接测序和定量CRC中出现的T细胞受体（TCR）库，提供了在流行病学背景下获得基本机制见解的机会。我们的目标是了解为什么适应性免疫反应在结直肠癌中差异如此之大，并利用这些信息来改善患者的预后。在这里，我们假设，临床，流行病学和遗传因素调节宿主免疫反应的强度和质量，并且这些因素独立地影响预后。此外，我们假设，在CRC肿瘤中的TIL数量和TCR克隆性是独立的预后因素。结合创新的高通量测序方法的TIL表征（immunoSEQ），全基因组关联研究（GWAS）的遗传变异影响淋巴细胞浸润的TME，和一个经典的流行病学调查的预后，我们将全面描述的流行病学的免疫应答的肿瘤4,000例患者在人群为基础的病例对照研究结直肠癌在北方以色列。我们将通过3个具体目标，确定在人群规模上调节宿主对CRC免疫反应的因素，并推进目前对CRC预后因素的理解。在目标1中，我们将使用传统的光学显微镜和immunoSEQ对来自结直肠癌分子流行病学（MECC）研究的4，000例原发性结直肠癌（CRC）中的T细胞浸润进行定量和表征。在目标2中，我们将研究经典流行病学变量、HLA位点特异性遗传变异和全基因组种系变异与4,000例原发性CRC中宿主免疫应答的定量指标之间的关联。在目标3中，我们将评估TIL数量、克隆性和任何新鉴定的预测免疫应答的遗传/HLA等位基因作为CRC总体和无病生存期的预后因素。将流行病学和遗传变量与肿瘤中宿主免疫应答的定量和定性指标相结合，可能揭示与免疫介导的组织特异性破坏相关的新分子和细胞特征。

 DESCRIPTION (provided by applicant): The immune system plays a key role in regulating the development and progression of colorectal cancer (CRC), and tumor infiltration by T lymphocytes is a highly informative prognostic factor for CRC outcome. Advances in screening and treatment have substantially improved survival from CRC over the past decade, but clinical outcomes still vary widely among patients with tumors diagnosed at the same TNM stage, and disease relapse occurs in 20-30% of patients with localized cancer. This suggests that traditional prognostic factors, including stage and tumor infiltrating lymphocytes (TIL) quantified by classical means of expert pathology review under light microscopy, lack sufficient granularity to predict patient outcome and to guide the optimal treatment choice for many patients. TILs can trigger preferential lysis of cancer cells by recognizing enhanced expression of abnormally expressed antigens presented in the context of HLA molecules, but the host and tumor factors regulating this adaptive immune response in the tumor microenvironment remain largely unexplored. We propose to address these gaps in knowledge by studying the factors regulating the immune response in an existing, population- based epidemiologic study of 4,000 colorectal cancer cases with essentially perfect clinical annotation and follow-up. A new technical advance now permits the direct sequencing and quantification of the T cell receptor (TCR) repertoire that arises within CRC, providing an opportunity to gain fundamental mechanistic insight within an epidemiologic context. Our goal is to understand why adaptive immune responses differ so dramatically across colorectal cancers, and to harness this information to improve patient outcomes. Here, we hypothesize that clinical, epidemiologic and genetic factors regulate the strength and the quality of the host immune response, and that these factors contribute independently to prognosis. Further, we hypothesize that TIL quantity and TCR clonality in CRC tumors are independent prognostic factors. Combining an innovative high-throughput sequencing approach for TIL characterization (immunoSEQ), a genome-wide association study (GWAS) of genetic variation influencing lymphocyte infiltration in the TME, and a classical epidemiologic investigation of prognosis, we will comprehensively describe the epidemiology of the hostimmune response in tumors from 4,000 patients within a population-based case-control study of CRC in northern Israel. We will identify factors that regulate the host immune response to CRC on a population scale, and advance the current understanding of prognostic factors for CRC, through 3 specific aims. In Aim 1, we will quantify and characterize T cell infiltration in 4,000 primary colorectal cancers (CRCs) from the Molecular Epidemiology of Colorectal Cancer (MECC) study using traditional light microscopy and immunoSEQ. In Aim 2, we will investigate the association of classic epidemiologic variables, HLA locus-specific genetic variation, and genome-wide germline variation with quantitative metrics of the host immune response in 4,000 primary CRCs. In Aim 3, we will evaluate TIL quantity, clonality, and any newly-identified genetic/HLA alleles predictive of immune response as prognostic factors for overall and disease-free survival from CRC. Combining epidemiologic and genetic variables with quantitative and qualitative metrics of the host immune response in the tumor may reveal novel molecular and cellular signatures associated with immune-mediated, tissue-specific destruction.