Innate anti-tumor immune responses

先天性抗肿瘤免疫反应

• 批准号: 8193740
• 负责人: Jack D Bui
• 金额: $ 31.36万
• 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/8193740
• 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

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. PUBLIC HEALTH RELEVANCE: This research addresses how the innate immune system attacks tumor cells. We are testing the idea that certain cytokines produced by the tumor cell itself can lead to activation of innate immune cells. Our studies will provide a method to enhance cancer treatment by harnessing the power of the immune system.

描述（由适用提供）：巨噬细胞和中性粒细胞等先天免疫细胞可以促进或阻碍肿瘤的生长，但尚不清楚这些相反的活性如何在肿瘤微环境中调节。该赠款的主要目的是阐明固有细胞被激活以破坏肿瘤细胞的机制。为了研究肿瘤如何激活先天免疫，我们产生了匹配的肿瘤细胞系组，这些肿瘤细胞系被免疫系统（称为回归体）拒绝或逐渐生长（称为Progressors），当将其移植到na¿ve中，野生型小鼠。我们进行了比较研究，以鉴定与逐渐生长的肿瘤相比，这些关键免疫系统成分富含被排斥的肿瘤。使用流式细胞仪，免疫组织化学和微阵列分析，我们确定了活化的巨噬细胞，中性粒细胞，一氧化氮和细胞因子IL-17D是肿瘤排斥的参与者。我们的具体目的试图了解这些细胞和分子相互作用以影响肿瘤排斥的机制。原理假设指出，肿瘤微环境中产生的IL-17D报告中性粒细胞并激活巨噬细胞，以通过一氧化氮的产生消除肿瘤细胞。具体目标1将研究IL-17D在塑造先天和适应性抗肿瘤反应中的作用。我们将调节肿瘤细胞中的IL-17D水平，并观察到对肿瘤生长和免疫细胞浸润的影响。特定的目标2将探索巨噬细胞如何通过在体外和体内测量巨噬细胞结核活动来促进肿瘤排斥。我们将比较从回归者与进度肿瘤中分离出的巨噬细胞。特定的目标3将检查回归肿瘤引起的中性粒细胞效应途径。这些研究将提高基于细胞因子的抗肿瘤免疫治疗方法的有效性，同时提供对先天性免疫细胞如何消除肿瘤的侵入性。 公共卫生相关性：本研究介绍了先天免疫系统如何攻击肿瘤细胞。我们正在测试这样的想法，即肿瘤细胞本身产生的某些细胞因子可以导致先天免疫细胞的激活。我们的研究将通过利用免疫系统的能力来提供一种增强癌症治疗方法的方法。