Variation in tumor-associated immune profiles and colorectal cancer outcomes

肿瘤相关免疫特征和结直肠癌结果的变化

• 批准号: 10684182
• 负责人: Stephanie L. Schmit
• 金额: $ 66.59万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684182
• 关键词: Accounting; Address; Admixture; African; African American; African American population; African ancestry; American; Aspirin; Autoimmune; Back; Biological; Biological Markers; Body mass index; C-reactive protein; CD8-Positive T-Lymphocytes; Caribbean region; Clinical; Clinical Data; Clonality; Colorectal Cancer; Communities; Cytotoxic T-Lymphocytes; DNA; Data; Development; Disparity; Epidemiologic Factors; Epidemiology; Ethnic Origin; Ethnic Population; European; Event; FDA approved; Genes; Genetic; Genetic Variation; Genotype; Goals; Hispanic; Immune; Immune checkpoint inhibitor; Immune response; Immunobiology; Immunofluorescence Immunologic; Immunologic Factors; Immunologics; Immunotherapy; Indigenous American; Inflammation; Inflammatory; Latino; Latino Population; Latinx; Latinx population; Link; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Microsatellite Instability; Minority; Minority Groups; Molecular Epidemiology; Molecular Epidemiology of Cancer; Natural Selections; Neoplasm Metastasis; Not Hispanic or Latino; Obesity; Outcome; Participant; Patient Self-Report; Play; Population; Population Heterogeneity; Predictive Factor; Prevention strategy; Prognostic Factor; Proteins; Protocols documentation; Puerto Rico; Race; Reaction; Research; Resources; Risk Factors; Role; Shapes; Site; Smoking; Spatial Distribution; Subgroup; T cell infiltration; T cell response; T-Cell Receptor; T-Lymphocyte; T-cell diversity; T-cell receptor repertoire; Testing; Tissue Microarray; Treatment outcome; Tumor-Infiltrating Lymphocytes; Tumor-associated macrophages; Variant; Woman; admixture mapping; biobank; cancer care; cancer health disparity; cancer therapy; caucasian American; cytokine; density; differential expression; exhaustion; experience; genetic architecture; genomic locus; immune cell infiltrate; immune function; liquid crystal polymer; malignant breast neoplasm; men; molecular subtypes; mortality; outcome disparities; patient population; pembrolizumab; prognostic; racial diversity; racial population; response; sociodemographic factors; survival disparity; translational potential; treatment response; treatment strategy; trend; tumor; tumor microenvironment; tumor-immune system interactions

Considerable variability in tumor-associated immune responses exists across racial/ethnic populations. These variations may explain part of the observed disparities in response to cancer therapies, particularly immunotherapy, and treatment outcomes. In colorectal cancer (CRC), the intensity and composition of tumor infiltrating lymphocytes (TIL) are established prognostic and predictive indicators. However, factors contributing to the diversity of TIL responses observed among CRCs remain largely unknown, and the influence of race/ethnicity and genetic ancestry have been underexplored. In a recent study comparing CRCs from African Americans and non-Hispanic Whites, differences in lymphocytic reactions were observed to partially explain the survival disparity between the two groups. No data is available for other racial/ethnic groups. Prior research has also been limited by relying solely on self-reported race/ethnicity, a significant limitation. Studies show that self-report does not fully or accurately reflect the genetic diversity present in admixed minority populations. We hypothesize that ancestral genetic architecture is important for shaping immune-related determinants of CRC outcomes given the differential efficiency of immune function observed across racial/ethnic groups. Studies in the genertically admixed Latinx population offer notable advantages including a unique opportunity to simultaneously tease out the contributions of multiple ancestral backgrounds (e.g. African, European, Indigenous American) to variability in immune function. Here, we will test the hypothesis that genetic ancestry is independently associated with differences in tumor-associated T cell profiles that contribute to CRC outcome disparities (i.e. observed across populations defined by ethnicity and by genetic ancestry) using existing resources from the Hispanic Colorectal Cancer Study, the Puerto Rico Biobank, the Total Cancer Care Protocol, and the Molecular Epidemiology of Colorectal Cancer Study . We will address three aims: (1) quantify CRC-associated T cell profiles in Latinxs from diverse genetic ancestral backgrounds using DNA- and protein-based approaches; (2) investigate the independent associations of genetic ancestry, epidemiologic factors, and clinical variables with T cell profiles in the tumor microenvironment of Latinx CRCs; and (3) compare CRC-associated T cell profiles between Latinx and NHW populations. This study is unique in leveraging the ancestral diversity of Latinos to understand the relationships between race/ethnicity, germline genetics, tumor immunobiology, and cancer disparities. Results will provide new avenues for understanding immunological factors contributing to disproportionate treatment response and mortality in diverse populations of patients with CRC.

种族/族裔人群之间存在肿瘤相关免疫反应的显着差异。 这些变化可能解释了响应癌症疗法的部分差异，特别是 免疫疗法和治疗结果。在结直肠癌（CRC）中，肿瘤的强度和组成 浸润淋巴细胞（TIL）是确定的预后和预测指标。但是，因素 在CRC中观察到的直到响应的多样性的贡献基本上是未知的，并且 种族/种族和遗传血统的影响还没有得到充实的态度。在最近的一项比较CRC的研究中 来自非裔美国人和非西班牙裔白人，观察到淋巴细胞反应的差异 部分解释了两组之间的生存差异。没有其他种族/种族的数据 组。先前的研究也受到限制，仅依靠自我报告的种族/种族，这是一个重要的 局限性。研究表明，自我报告并不能完全或准确地反映出存在的遗传多样性 混合少数族裔人口。我们假设祖先的遗传结构对于塑造很重要 鉴于观察到的免疫功能的差异效率，CRC结果的免疫相关决定因素 跨种族/族裔。在基因混合拉丁裔人群中的研究提供了显着优势 包括一个独特的机会，同时取笑多个祖先背景的贡献 （例如非洲，欧洲，土著美国人），以使免疫功能变异。在这里，我们将测试 假设遗传血统与肿瘤相关的T细胞的差异独立相关 导致CRC结果差异的概况（即，在种族和种族定义的人群中观察到 通过遗传血统）使用西班牙裔大肠癌研究中的现有资源，波多黎各 生物库，总癌症护理方案和结直肠癌研究的分子流行病学 。我们 将解决三个目的：（1）量化来自不同遗传祖先的拉丁裔与CRC相关的T细胞谱 使用基于DNA和蛋白质的方法的背景； （2）调查独立关联 遗传祖先，流行病学因素和临床变量具有T细胞谱的肿瘤中的临床变量 Latinx CRC的微环境； （3）比较Latinx和NHW之间与CRC相关的T细胞谱 人群。这项研究在利用拉丁美洲人的祖先多样性方面是独一无二的 种族/种族，种系遗传学，肿瘤免疫生物学和癌症差异之间的关系。 结果将为理解免疫因素提供新的途径，导致不成比例 CRC患者不同种群的治疗反应和死亡率。