Defining the inflammatory signals that regulate CD8+ T cell recruitment and function in colorectal cancer

定义调节结直肠癌中 CD8 T 细胞募集和功能的炎症信号

• 批准号: 9759795
• 负责人: Tessa Bergsbaken
• 金额: $ 18.9万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759795
• 关键词: Address; Area; Automobile Driving; Award; CD8-Positive T-Lymphocytes; CD8B1 gene; CXCR3 gene; Cancer Immunology Science; Cells; Collaborations; Colorectal Cancer; Colorectal Neoplasms; Cues; Development; Environment; Faculty; Feedback; Fred Hutchinson Cancer Research Center; Funding; General Population; Goals; Heterogeneity; Immunology; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Infiltrate; Institution; Integration Host Factors; Integrins; Intestinal Neoplasms; Intestines; Invaded; Knowledge; Laboratories; Laboratory Research; Lamina Propria; Lead; Ligands; Malignant Neoplasms; Mediating; Microbe; Modeling; Natural Immunity; Neoplasm Metastasis; Pathogenesis; Pathogenicity; Phenotype; Population; Population Control; Population Sizes; Positioning Attribute; Postdoctoral Fellow; Production; Reagent; Research; Role; Scientist; Secure; Signal Transduction; Solid; Solid Neoplasm; T cell response; T-Lymphocyte; Technical Expertise; Tissues; Tumor Antigens; Tumor Tissue; Tumor-infiltrating immune cells; Universities; Washington; Work; adaptive immune response; base; career; chemokine receptor; colon tumorigenesis; colorectal cancer risk; cytokine; cytotoxic; disorder control; enhancing factor; experimental study; insight; microbial; microorganism; mouse model; post-doctoral training; programs; recruit; response; tenure track; tumor; tumor growth; tumor microenvironment; tumor progression

My current research has focused on the CD8+ T cell response to infection within the tissue and how this is influenced by local inflammation. This application builds on my prior work, and seeks to examine the role of inflammation in directing productive tissue resident T cell responses to colorectal cancer. My immediate career goal is to acquire an independent faculty position, and subsequently, to lead a research program that focuses on T cell responses that develop in response to both pathogenic microorganisms and solid tumors in the intestinal tissue. The University of Washington is an excellent environment for training postdoctoral fellows to become independent research scientists. I have been supported by Dr. Bevan and the Department of Immunology in my research and professional development. The department has provided me with the opportunity to present my research and receive feedback, attend research seminars in a variety areas including cancer immunology, and encourages collaboration with affiliated institutions including Fred Hutchinson Cancer Research Center. Many of Dr. Bevan's trainees have gone on to establish successful research laboratories, and I believe I have also received the support and guidance necessary to secure a tenure-track faculty position. It is well established that CD8+ T cell infiltration into solid malignancies, including colorectal tumors, positively correlates with tumor control. The majority of intestinal CD8+ T cells are CD103+; however, after infection, a sizable population of CD103– cells develops in the lamina propria in response to inflammatory cues. We hypothesize that a CD103– CD8+ T cell population develops in the intestine during colorectal tumorigenesis and provides superior control of tumor growth, and that inflammation within the tumor microenvironment promotes the development and function of this T cell population. This proposal aims to establish a mouse model of colorectal tumor formation with a defined tumor-associated antigen that will allow us to address questions about the phenotype and function of tumor-specific CD8+ T cells, the role of CXCR3 in their recruitment into the tumor, and the role of IL-33 produced by tumor tissue in promoting effector function. I believe my earlier research addressing innate immunity and its influence on adaptive immune responses in the tissue provides me with the technical expertise and scientific knowledge to examine the role of inflammation in driving adaptive immune responses in colorectal tumor tissue. The funding provided by this award would provide me with the opportunity to generate reagents and perform the necessary experiments to address these questions and develop this new area of research in my laboratory.

我目前的研究集中于CD8+ T细胞对感染的反应 组织及其如何受到局部注入的影响。此应用程序建立在 我先前的工作，并试图检查炎症在指导产品中的作用 组织居民T细胞对结直肠癌的反应。我的直接职业目标是 获得独立的教师职位，随后以领导研究计划 这重点是响应两种致病性而发展的T细胞反应 肠组织中的微生物和实体瘤。华盛顿大学 是培训博士后研究员独立的绝佳环境 研究科学家。我得到了Bevan博士和部门的支持 我的研究和专业发展中的免疫学。该部门有 为我提供了介绍我的研究并收到反馈的机会，参加 在包括癌症免疫学在内的各个领域的研究中心，并鼓励 与弗雷德·哈钦森癌症研究在内的会员机构的合作 中心。 Bevan博士的许多学员都继续建立成功的研究 实验室，我相信我也得到了必要的支持和指导 确保任职教师职位。 众所周知，CD8+ T细胞浸润到固体恶性肿瘤中，包括 结直肠肿瘤，与肿瘤控制正相关。大多数肠道 CD8+ T细胞为CD103+；但是，感染后，大量的CD103-细胞群 在炎症提示的响应中，在椎板层中发展。我们假设一个 CD103– CD8+ T细胞种群在结直肠肿瘤发生过程中的肠道发展 并提供了对肿瘤生长的高度控制，并在肿瘤内感染 微环境促进了该T细胞种群的发展和功能。这 提案旨在建立与定义的结直肠肿瘤形成的小鼠模型 肿瘤相关的抗原，这将使我们能够解决有关表型的问题 肿瘤特异性CD8+ T细胞的功能，CXCR3在其募集中的作用 肿瘤以及肿瘤组织在促进效应功能中产生的IL-33的作用。 我相信我较早的研究针对先天免疫及其对适应性的影响 组织中的免疫反应为我提供了技术专业知识和科学知识 知识以检查炎症在推动适应性免疫反应中的作用 结直肠肿瘤组织。该奖项提供的资金将为我提供 生成试剂并执行必要的实验以解决的机会 这些问题并在我的实验室中发展了新的研究领域。