Innate anti-tumor immune responses

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阐明先天细胞被激活以摧毁肿瘤细胞的机制。为了研究肿瘤如何激活先天免疫，我们已经产生了一组匹配的肿瘤细胞系，当移植到同基因的，幼稚的，野生型小鼠时，这些细胞系被免疫系统排斥（称为消退）或逐渐生长（称为进展）。我们已经进行了比较研究，以确定与进行性生长的肿瘤相比，在经历排斥的肿瘤中富集的关键免疫系统成分。使用流式细胞术，免疫组织化学，和微阵列分析，我们已经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-17 D参与肿瘤排斥反应。我们的具体目标是寻求了解这些细胞和分子相互作用以实现肿瘤排斥的机制。原理假说指出，肿瘤微环境中产生的IL-17 D募集嗜中性粒细胞并激活巨噬细胞以通过一氧化氮产生消除肿瘤细胞。具体目标1将研究IL-17 D在形成先天性和适应性抗肿瘤应答中的作用。我们将调节肿瘤细胞中的IL-17 D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将通过测量巨噬细胞在体外和体内的杀肿瘤活性来探索巨噬细胞如何促进肿瘤排斥。我们将比较从消退与进展肿瘤中分离的巨噬细胞。具体目标3将检查由消退肿瘤引起的中性粒细胞效应子途径。这些研究将增强基于精氨酸的抗肿瘤免疫方法的功效，同时为先天免疫细胞如何消除正在发展的肿瘤提供进展。

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.