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

点击翻译按钮获取中文摘要

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.