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.

我目前的研究集中在CD 8 + T细胞对感染的反应， 以及局部炎症对组织的影响。此应用程序基于 我以前的工作，并试图检查炎症在指导生产力的作用， 组织驻留T细胞对结直肠癌的反应。我的职业目标是 获得一个独立的教师职位，并随后领导一个研究项目 它关注的是T细胞反应， 肠道组织中的微生物和实体肿瘤。华盛顿大学 是培养博士后独立的良好环境 研究科学家。我得到了贝文博士和 免疫学在我的研究和专业发展。新闻部 为我提供了展示我的研究并接收反馈的机会，参加 包括癌症免疫学在内的各个领域的研究研讨会，并鼓励 与包括弗雷德哈钦森癌症研究在内的附属机构合作 中心贝文博士的许多受训者都成功地进行了研究 我相信我也得到了必要的支持和指导， 争取到一个终身教职 已经确定，CD 8 + T细胞浸润到实体恶性肿瘤中，包括 结直肠肿瘤，与肿瘤控制呈正相关。大多数肠道 CD 8 + T细胞是CD 103 +;然而，在感染后，相当大的CD 103-细胞群体 在固有层中响应炎症信号而发展。我们假设 结直肠肿瘤发生过程中肠道内CD 103-CD 8 + T细胞群的形成 并提供对肿瘤生长的上级控制， 微环境促进该T细胞群体的发育和功能。这 一项提案旨在建立一种具有定义的结肠直肠肿瘤形成的小鼠模型， 肿瘤相关抗原，这将使我们能够解决有关表型的问题 和功能的肿瘤特异性CD 8 + T细胞，CXCR 3在其招募的作用， 肿瘤，以及肿瘤组织产生的IL-33在促进效应子功能中的作用。 我相信我之前的研究解决了先天免疫及其对适应性免疫的影响， 组织中的免疫反应为我提供了技术专长和科学知识， 研究炎症在驱动适应性免疫反应中的作用的知识， 结直肠肿瘤组织。这个奖项提供的资金将为我提供 有机会生成试剂并进行必要的实验，以解决 这些问题，并在我的实验室里发展这个新的研究领域。