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Innate anti-tumor immune responses

先天性抗肿瘤免疫反应

基本信息

批准号：
9052306
负责人：
Jack D Bui
金额：
$ 6.65万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-02 至 2017-05-31
项目状态：
已结题

项目摘要

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）：先天免疫细胞如巨噬细胞和中性粒细胞可以促进或阻碍肿瘤生长，但目前尚不清楚这些相反的活性是如何在肿瘤微环境中调节的。这项资助的主要目的是阐明先天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，我们已经产生了匹配的肿瘤细胞系，这些细胞系在移植到同基因的、无基因的野生型小鼠体内时，被免疫系统排斥（称为退化）或逐渐生长（称为进展）。我们已经进行了比较研究，以确定在经历排斥反应的肿瘤中富集的关键免疫系统成分，与进行性生长的肿瘤相比。通过流式细胞术、免疫组织化学和微阵列分析，我们发现活化的巨噬细胞、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以影响肿瘤排斥的机制。主要假设认为，在肿瘤微环境中产生的IL-17D招募中性粒细胞并激活巨噬细胞，通过产生一氧化氮来消除肿瘤细胞。特异性目的1将研究IL-17D在形成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IL-17D水平，观察其对肿瘤生长和免疫细胞浸润的影响。特异性目的2将通过测量巨噬细胞体外和体内的杀肿瘤活性来探讨巨噬细胞如何促进肿瘤排斥反应。我们将比较从退行性肿瘤和进展性肿瘤中分离的巨噬细胞。特异性目的3将检查中性粒细胞效应途径是由退化性肿瘤引起的。这些研究将增强基于细胞因子的抗肿瘤免疫治疗方法的有效性，同时为先天免疫细胞如何消除发展中的肿瘤提供研究进展。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Nrf2 Induces IL-17D to Mediate Tumor and Virus Surveillance.

DOI：
10.1016/j.celrep.2016.07.075
发表时间：
2016-08-30
期刊：
Cell reports
影响因子：
8.8
作者：
Saddawi-Konefka R;Seelige R;Gross ET;Levy E;Searles SC;Washington A Jr;Santosa EK;Liu B;O'Sullivan TE;Harismendy O;Bui JD
通讯作者：
Bui JD

Cell-cell fusion as a mechanism of DNA exchange in cancer.