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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。头颈部鳞状细胞癌（SCCHN）的一个亚群在大约60%的病例中与人乳头瘤病毒（HPV）感染有关，这为免疫治疗提供了一个潜在的靶点。然而，已知SCCHN肿瘤（所有部位）也严重损害免疫反应，导致T细胞特异性分子改变。导致这种T细胞能量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：“由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精氨酸酶，从而导致T细胞能量状态。”阻断诱导精氨酸酶产生的信号将导致保护性免疫反应，并增强免疫治疗对SCCHN的疗效。”这项工作将研究SCCHN中诱导精氨酸酶产生的机制，细胞因子和COX-2的作用，并将测试阻断精氨酸酶或前列腺素是否会阻止精氨酸酶的产生和诱导T细胞信号转导缺陷。我们将使用体外和动物模型来确定产生精氨酸酶1的髓细胞在诱导T细胞信号转导改变中的作用。我们将确定哪些肿瘤衍生因子刺激精氨酸酶的产生。使用小鼠SCCHN模型，我们将测试各种阻断精氨酸酶产生的治疗方法。我们希望发现前列腺素在SCCHN中诱导精氨酸酶，因此将进行一项先导临床试验，用COX-2抑制剂治疗一组SCCHN患者，并利用特异性和新颖的分子终点（如精氨酸酶1表达和T细胞信号转导分子的变化）监测其效果。这个项目代表了一个完整的转化研究项目，从实验室观察到动物模型研究和患者样本研究，然后开发一种新的临床试验，使用独特的分子标记来测量常用治疗剂的效果。

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.