Innate anti-tumor immune responses

先天性抗肿瘤免疫反应

• 批准号: 8894151
• 负责人: Jack D Bui
• 金额: $ 6.22万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-02 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8894151
• 关键词: Address; Affect; Animal Model; Biological Models; Carcinogens; Cell physiology; Cells; Characteristics; Comparative Study; Flow Cytometry; Goals; Grant; Human; Immune; Immune response; Immune system; Immunohistochemistry; Immunotherapeutic agent; Immunotherapy; Infiltration; Investigation; Lead; Leukocytes; Malignant Neoplasms; Measures; Mediating; Methods; Microarray Analysis; Mus; Natural Immunity; Nitric Oxide; Participant; Pathway interactions; Production; Property; Recruitment Activity; Research; Role; Shapes; Signal Transduction; System; Testing; Transplantation; Tumor Cell Line; Wild Type Mouse; base; cancer therapy; cytokine; immune function; in vitro activity; in vivo; macrophage; neoplastic cell; neutrophil; overexpression; response; sarcoma; tumor; tumor growth; tumor microenvironment

DESCRIPTION (provided by applicant): Innate immune cells such as macrophages and neutrophils can promote or hinder tumor growth, but it is not known how these opposing activities are regulated in the tumor microenvironment. The major goal of this grant is to elucidate the mechanisms by which innate cells are activated to destroy tumor cells. To study how tumors may activate innate immunity, we have produced matched sets of tumor cell lines that are rejected by the immune system (termed regressors) or grow progressively (termed progressors) when transplanted into syngeneic, na�ve, wild-type mice. We have performed comparative studies to identify key immune system components that are enriched in tumors that undergo rejection compared to tumors that grow progressively. Using flow cytometry, immunohistochemistry, and microarray analysis, we have identified activated macrophages, neutrophils, nitric oxide, and the cytokine IL-17D as participants in tumor rejection. Our specific aims seek to understand the mechanism by which these cells and molecules interact to effect tumor rejection. The principle hypothesis states that IL-17D produced in the tumor microenvironment recruits neutrophils and activates macrophages to eliminate tumor cells via nitric oxide production. Specific aim 1 will study the role of IL-17D in shaping innate and adaptive anti-tumor responses. We will modulate IL-17D levels in tumor cells and observe the effect on tumor growth and immune cell infiltration. Specific aim 2 will explore how macrophages can promote tumor rejection by measuring macrophage tumoricidal activity in vitro and in vivo. We will compare macrophages isolated from regressor versus progressor tumors. Specific aim 3 will examine neutrophil effector pathways that are elicited by regressor tumors. These studies will enhance the efficacy of cytokine-based anti-tumor immunotherapeutic approaches while providing inroads into how innate immune cells can eliminate developing tumors.

描述（由申请人提供）：先天免疫细胞（例如巨噬细胞和中性粒细胞）可以促进或阻碍肿瘤生长，但尚不清楚这些相反的活性在肿瘤微环境中是如何调节的。这项资助的主要目标是通过以下方式阐明其机制。为了研究肿瘤如何激活先天免疫，我们产生了一组匹配的肿瘤细胞系，这些细胞系被免疫系统排斥（称为回归细胞）或逐渐生长。当移植到同源、幼稚的野生型小鼠中时，我们使用流式细胞术、免疫组织化学和微阵列进行了比较研究，以确定经历排斥的肿瘤中富含的关键免疫系统成分。通过分析，我们确定了巨噬细胞、中性粒细胞、一氧化氮和细胞因子 IL-17D 参与肿瘤排斥反应，我们的具体目标是了解这些细胞和分子相互作用的机制。假设原理指出，肿瘤微环境中产生的 IL-17D 会招募中性粒细胞并激活巨噬细胞，通过一氧化氮的产生来消除肿瘤细胞。具体目标 1 将研究 IL-17D 在塑造先天性和适应性抗肿瘤细胞中的作用。我们将调节肿瘤细胞中的 IL-17D 水平并观察对肿瘤生长和免疫细胞浸润的影响。具体目标 2 将探讨巨噬细胞如何通过测量来促进肿瘤排斥。我们将比较从消退肿瘤和进展肿瘤中分离的巨噬细胞的杀肿瘤活性，具体目标 3 将检查消退肿瘤引起的中性粒细胞效应途径，这些研究将增强基于细胞因子的抗肿瘤免疫治疗方法的功效。同时进一步研究先天免疫细胞如何消除正在形成的肿瘤。