Project 2: Racial differences in host immune response and gastric carcinogenesis: Translating underlying biology to promote gastric cancer interception

项目2：宿主免疫反应和胃癌发生的种族差异：转化基础生物学以促进胃癌拦截

• 批准号: 10037509
• 负责人: MEIRA EPPLEIN
• 金额: $ 31.45万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10037509
• 关键词: 3-Dimensional; Adaptive Immune System; Address; African American; Antibodies; Antibody Response; Antigens; Atrophic Gastritis; Biological; Biology; Cancer Etiology; Cause of Death; Cells; Chronic Gastritis; Clinical; Coculture Techniques; Complex; Cytotoxic T-Lymphocytes; Cytotoxin; Data; Data Set; Dysplasia; Epithelial; Epithelium; Event; Foundations; Future; Gastric mucosa; Gastritis; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Helicobacter Infections; Helicobacter pylori; IL8 gene; Immune; Immune response; Incidence; Individual; Infection; Inflammatory; Intercept; Interleukin-1 beta; Interleukin-10; Interleukin-17; Interleukin-6; Intestinal Intraepithelial Neoplasia; Intestinal Metaplasia; Knowledge; Lesion; Malignant Neoplasms; Mediating; Metaplasia; Not Hispanic or Latino; Organoids; Pathogenesis; Pathologic; Patients; Pattern; Pepsinogens; Prevention; Process; Race; Regulatory T-Lymphocyte; Retrospective cohort; Risk; Risk Factors; Risk Marker; Risk stratification; Screening for Gastric Cancer; Serum; Specimen; Stomach; System; T cell response; TNF gene; Testing; Tissue Sample; Tissues; Transforming Growth Factor beta; Translating; Tumor-infiltrating immune cells; Virulence; Virulence Factors; Virulent; advanced disease; base; cancer health disparity; cancer prevention; cancer risk; clinical practice; cytokine; cytotoxic; disparity reduction; gastric carcinogenesis; high risk; improved; individualized prevention; macrophage; malignant stomach neoplasm; men; mortality; mortality disparity; novel; patient population; population based; programmed cell death ligand 1; prospective; racial difference; racial disparity; response; screening; serological marker; surveillance strategy; translational approach

ABSTRACT – Project 2 Gastric cancer is responsible for the third largest disparity in cancer incidence rates between Non-Hispanic African Americans and whites. More importantly, African Americans are more than twice as likely to die from gastric cancer than whites – the highest mortality disparity of any cancer. As a highly fatal cancer, gastric cancer is the 6th leading cause of death from cancer among African American men. Most gastric cancers are caused by Helicobacter pylori (H. pylori) infection, which is more common among African Americans than whites. Improved understanding of the immune response to H. pylori has not translated into advances in screening, surveillance, or cancer prevention. Indeed, Currently, the US does not have a strategy for gastric cancer screening and surveillance. A cascade of events leads to gastric cancer, initiated by H. pylori infection, followed by changes including chronic gastritis, intestinal metaplasia (IM), dysplasia, and cancer. Currently, little is known about how racially mediated differences in response to H. pylori infection might result in increased gastric cancer risk. It is known, for instance, that H. pylori virulence factors such as cytotoxic associated geneA, CagA, as well as more virulent forms of vacuolating cytotoxin A, VacA, interfere with the host adaptive immune system to allow H. pylori colonization in gastric mucosa. Moreover, certain CagA/VacA genotypes are associated with increased gastric inflammation and epithelial degeneration. Our own preliminary data demonstrate that African Americans have increased antibody responses to CagA and VacA, which correlate with increased risk of metaplasia and dysplasia. However, the mechanisms through which race-associated genetic factors, such as IL-1β polymorphism, relate to other virulence factors in the progression of precursor lesions and the pathogenesis of gastric cancer are unknown. Our goal is to address these knowledge gaps and translate biologic findings into new screening and surveillance strategies for clinical practice in order to address racial disparities and improve survival related to gastric cancer. We hypothesize that H. pylori infection in African Americans is more likely to result in an immune response that increases risk of intestinal metaplasia, dysplasia and evasion of cytotoxic T cell response, explaining the underlying disparity in stomach cancer incidence and mortality. We will create a retrospective cohort and test the hypothesis that racial differences in tissue-based immune response along the gastric carcinogenesis cascade correlate with more advanced disease (Aim 1); and prospectively compare racial differences in host response to H. pylori in fresh serum and tissue samples (Aim 2). This Project will develop novel risk markers to be applied to a risk-stratification strategy that incorporates H. pylori virulence factors and the immune-based signature found in high-risk African Americans, as a key step toward reducing the disparity gap in gastric cancer screening, surveillance, and prevention.

摘要 – 项目 2 胃癌是非西班牙裔癌症发病率第三大差异的原因 非裔美国人和白人。更重要的是，非裔美国人死于此病的可能性是非裔美国人的两倍多 胃癌的死亡率高于白人——这是所有癌症中死亡率差距最大的。胃癌作为一种致死率极高的癌症 是非裔美国男性癌症死亡的第六大原因。大多数胃癌是由 幽门螺杆菌 (H. pylori) 感染在非裔美国人中比白人更常见。改进 对幽门螺杆菌免疫反应的了解尚未转化为筛查、监测、 或预防癌症。事实上，目前美国还没有胃癌筛查策略， 监视。由幽门螺杆菌感染引发的一系列事件导致胃癌，随后发生变化 包括慢性胃炎、肠化生 (IM)、发育不良和癌症。目前，人们对如何 种族介导的对幽门螺杆菌感染反应的差异可能会导致胃癌风险增加。这是 例如，已知幽门螺杆菌毒力因子如细胞毒性相关基因 A、CagA 以及更多 有毒形式的空泡细胞毒素 A (VacA) 会干扰宿主适应性免疫系统，从而允许幽门螺杆菌 胃粘膜定植。此外，某些 CagA/VacA 基因型与胃溃疡增加有关。 炎症和上皮变性。我们自己的初步数据表明，非裔美国人 对 CagA 和 VacA 的抗体反应增加，这与化生和化生风险增加相关 发育不良。然而，种族相关遗传因素（例如 IL-1β）的机制 多态性，与前体病变进展和发病机制中的其他毒力因子有关 胃癌的发生尚不清楚。我们的目标是解决这些知识差距并转化生物学发现 纳入临床实践的新筛查和监测策略，以解决种族差异和 提高与胃癌相关的生存率。我们假设非洲裔美国人中幽门螺杆菌感染率更高 可能会导致免疫反应，增加肠化生、发育异常和逃避免疫的风险 细胞毒性 T 细胞反应，解释了胃癌发病率和死亡率的根本差异。我们将 创建一个回顾性队列并检验以下假设：基于组织的免疫反应存在种族差异 沿着胃癌发生级联与更晚期的疾病相关（目标 1）；并前瞻性地 比较新鲜血清和组织样本中宿主对幽门螺杆菌反应的种族差异（目标 2）。本项目 将开发新的风险标记，应用于纳入幽门螺杆菌毒力的风险分层策略 因素和在高风险非裔美国人中发现的基于免疫的特征，作为减少风险的关键一步 胃癌筛查、监测和预防方面的差距。