LSUHSC COBRE: PROJ 1: TOLERANCE MECHANISMS IN HEAD & NECK CANCER

LSUHSC COBRE：项目 1：头部的公差机制

• 批准号: 7382263
• 负责人: Jill Gilbert
• 金额: $ 19.76万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382263
• 关键词: LSUHSC; COBRE; PROJ; TOLERANCE; MECHANISMS

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A subset of Squamous-Cell carcinomas of the head and neck (SCCHN) are associated with infection by human papilloma virus (HPV) in approximately 60% of cases, providing a potential target for immunotherapy. However, SCCHN tumors (all sites) are also known to severely impair the immune response causing specific molecular alterations in T cells. The mechanisms leading to this state of T cell anergy are a subject of much research. The preliminary data presented here supports the hypothesis that "prostaglandin and/or cytokines produced by SCCHN tumors induce arginase in immature dendritic cells which results in a state of T cell anergy. Blocking signals that induce arginase production will lead to a protective immune response and enhance the efficacy of immunotherapy against SCCHN." The proposed work will study the mechanisms that induce arginase production in SCCHN, the role of cytokines and COX-2 and will test whether blocking arginase or prostaglandin prevents the production of arginase and the induction of T cell signal transduction defects. We will use in vitro and animal models to determine the role of arginase 1 producing myeloid cells in the induction of T cell signal transduction alterations. We will determine what tumor derived factors stimulate arginase production. Using a murine model of SCCHN we will test various therapeutic approaches to block arginase production. We expect to find that prostaglandins induce arginase in SCCHN and will therefore conduct a pilot clinical trial treating a cohort of patients with SCCHN with COX-2 inhibitors and monitoring its effect using specific and novel molecular endpoints such as arginase 1 expression and changes in T cell signal transduction molecules. This project represents a full translational research program from a laboratory observation to the study of animal models and the study of patient samples, followed by the development of a novel clinical trial using unique molecular markers to measure the effect of a commonly used therapeutic agent.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。头颈部鳞状细胞癌（SCCHN）的一个子集与约60%病例中的人乳头状瘤病毒（HPV）感染相关，为免疫治疗提供了潜在的靶点。然而，SCCHN肿瘤（所有部位）也已知会严重损害免疫反应，导致T细胞中的特定分子改变。导致这种T细胞无反应性状态的机制是许多研究的主题。本文提供的初步数据支持以下假设：“SCCHN肿瘤产生的前列腺素和/或细胞因子诱导未成熟树突状细胞中的过氧化物酶，导致T细胞无反应性状态。阻断诱导β-淀粉酶产生的信号将导致保护性免疫应答，并增强针对SCCHN的免疫治疗的功效。“这项拟议的工作将研究诱导SCCHN中辅酶A酶产生的机制、细胞因子和考克斯-2的作用，并将测试阻断辅酶A酶或前列腺素是否会阻止辅酶A酶的产生和T细胞信号转导缺陷的诱导。我们将使用体外和动物模型，以确定在T细胞信号转导改变的诱导中的作用，β-淀粉样蛋白酶1生产髓样细胞。我们将确定哪些肿瘤衍生因子刺激β-淀粉酶的产生。使用SCCHN的小鼠模型，我们将测试各种治疗方法来阻断β-内酰胺酶的产生。我们期望发现，胡枝子素诱导SCCHN中的辅酶Ⅰ酶，因此将进行一项试点临床试验，用考克斯-2抑制剂治疗一组SCCHN患者，并使用特异性和新的分子终点（如辅酶Ⅰ酶1表达和T细胞信号转导分子的变化）监测其效果。该项目代表了一个完整的转化研究计划，从实验室观察到动物模型的研究和患者样本的研究，然后开发一种新的临床试验，使用独特的分子标记物来测量常用治疗药物的效果。