Functions of caspase-8 mutations in development of head and neck cancer and anti-tumor immunity

Institution:	University of California, San Francisco
Investigator(s):	Zhibin Cui,
Award Cycle:	2019 (Cycle 29)	Grant #: T29FT0328	Award: $247,872
Subject Area:	Oral Disease and Dental Health
Award Type:	Postdoctoral Fellowship Awards

Abstracts

Initial Award Abstract

Head and neck squamous cell carcinoma (HNSCC) is a major health concern in the United States and worldwide. Nearly 1 out of every 10 cases of HNSCC has been found to have a mutation in a gene named caspase-8. The normal, nonmutated caspase-8 protein is known to play an important role in mediating cell death when cells are under stress. Additionally, caspase-8 plays a unique role in promoting the production of cytokines. These cytokines modulate the activity and production of immune cells and help the tumor cells escape elimination by our immune system. However, little is known about the role that HNSCC-associated caspase-8 gene mutations play in regulating anti-tumor immunity and how this mechanism impact tumorigenesis and progression of HNSCC. Three Aims are proposed here to determine whether caspase-8 gene mutations affect cytokine production and the destiny of immune cells in HNSCC tumors, and how these changes influence HNSCC initiation and progression. In Aim 1, I will study the roles of caspase-8 mutations in cell death and cytokine production in an in vitro cultured human cancer cell line, in which, normal caspase-8 (wild-type) will be modified to different mutant forms. In Aim 2, I will further determine how caspase-8 mutations impact cytokine production and modulate the production and activity of immune cells in mice inoculated with HNSCC cells expressing caspase-8 mutant proteins. In Aim 3, I will engineer a caspase-8 mutation into mice and determine the impact on development of HNSCC cancers in these mice following exposure to a chemical carcinogen similar to those found in tobacco smoke. Accomplishment of my project will allow me to determine whether the caspase-8 mutations frequently found in HNSCC play an important role in regulating anti-tumor immunity and HNSCC development. The ultimate goal for this study is to provide new diagnostic and prognostic markers to facilitate the development of new therapeutic strategies for patients with tobacco-associated HNSCC.