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: 10306076
• 负责人: Stephanie L. Schmit
• 金额: $ 73.69万
• 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/10306076
• 关键词: Accounting; Address; Admixture; African; African American; Aspirin; Back; Biological; Biological Markers; Body mass index; C-reactive protein; CD8-Positive T-Lymphocytes; Caribbean region; Central American; Clinical; Clinical Data; Clonality; Colorectal Cancer; Communities; Cytotoxic T-Lymphocytes; DNA; Data; Development; Epidemiologic Factors; Epidemiology; Ethnic Origin; Ethnic group; European; Event; FDA approved; Genes; Genetic; Genetic Variation; Genotype; Goals; Hispanics; Immune; Immune checkpoint inhibitor; Immune response; Immunobiology; Immunofluorescence Immunologic; Immunologic Factors; Immunologics; Immunotherapy; Indigenous American; Inflammatory; Latino; Latinx; Link; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Microsatellite Instability; Microsatellite Repeats; 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 response; T-Cell Receptor; T-Lymphocyte; T-cell diversity; T-cell receptor repertoire; Testing; Tissue Microarray; Treatment outcome; Tumor-Infiltrating Lymphocytes; Tumor-associated macrophages; Tumor-infiltrating immune cells; Variant; Woman; admixture mapping; autoimmune inflammation; base; biobank; cancer care; cancer health disparity; cancer therapy; caucasian American; cytokine; density; differential expression; exhaustion; experience; genetic architecture; genetic association; genomic locus; immune function; liquid crystal polymer; malignant breast neoplasm; men; molecular subtypes; mortality; patient population; pembrolizumab; prognostic; racial and ethnic; racial diversity; response; sociodemographic factors; survival disparity; 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.

不同种族/民族人群中肿瘤相关免疫反应存在相当大的差异。 这些差异可以解释部分观察到的对癌症治疗反应的差异，特别是 免疫疗法和治疗结果。在结直肠癌 (CRC) 中，肿瘤的强度和成分 浸润淋巴细胞（TIL）是既定的预后和预测指标。然而，因素 CRC 中观察到的 TIL 反应多样性的贡献仍然很大程度上未知，并且 种族/族裔和遗传血统的影响尚未得到充分探索。在最近的一项比较 CRC 的研究中 从非裔美国人和非西班牙裔白人中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/民族的数据 组。先前的研究也因仅依赖自我报告的种族/民族而受到限制，这是一个重要的因素 局限性。研究表明，自我报告并不能完全或准确地反映个体中存在的遗传多样性。 少数民族人口杂居。我们假设祖先遗传结构对于塑造 鉴于观察到的免疫功能效率差异，结直肠癌结果的免疫相关决定因素 跨种族/族裔群体。对普遍混合的拉丁裔人群的研究具有显着的优势 包括一个独特的机会，可以同时梳理出多个祖先背景的贡献 （例如非洲、欧洲、美洲原住民）免疫功能的变异。在这里，我们将测试 假设遗传血统与肿瘤相关 T 细胞的差异独立相关 导致 CRC 结果差异的概况（即在按种族和群体定义的人群中观察到的） 通过遗传血统）利用波多黎各西班牙裔结直肠癌研究的现有资源 生物样本库、全面癌症护理方案和结直肠癌分子流行病学研究 。我们 将实现三个目标：(1) 量化来自不同遗传祖先的拉丁裔中与 CRC 相关的 T 细胞谱 使用基于 DNA 和蛋白质的方法的背景； （二）调查独立协会 遗传血统、流行病学因素以及肿瘤中 T 细胞谱的临床变量 拉丁裔 CRC 的微环境； (3) 比较拉丁裔和 NHW 之间的 CRC 相关 T 细胞谱 人口。这项研究的独特之处在于利用拉丁裔的祖先多样性来了解 种族/民族、种系遗传学、肿瘤免疫生物学和癌症差异之间的关系。 结果将为理解导致不成比例的免疫因素提供新途径 不同人群的 CRC 患者的治疗反应和死亡率。