Date of Award

1-1-2011

Embargo Period

1-1-2025

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

A. Haque

Second Advisor

Laura Kasman

Third Advisor

N. Sutkowski

Fourth Advisor

Scott Tomlinson

Fifth Advisor

Christina Voelkel-Johnson

Abstract

Melanoma is the 6th most common cancer is the United States and accounts for 79% of skin cancer related deaths. While treatments such as surgery, radiation, and chemotherapy have been effective in dealing this disease in its early stages, these treatments often fail in treating late stage metastatic melanoma. Immunotherapies have been shown successful in treating a small percentage of patients with late stage melanoma, but these treatments do not provide a long-lasting CD8+ response to effectively clear the tumor. The majority of the melanoma cells either express or can be induced to express HLA class II proteins. An optimum presentation of HLA class II proteins is essential for activation of CD4+ T cells, which provide a sustained killing of malignant tumors by activating cytotoxic CD8+T cells. Our laboratory has also shown that melanoma cells express very low to undetectable levels of Gamma-interferon Inducible Lysosomal Thiol-reductase (GILT). The absence of GILT perturbs HLA class II antigen processing and presentation in melanoma cells. Our recent data suggest that GILT expression may restore immune recognition of melanoma cells via HLA class II molecules. Here, melanoma cells were successfully transfected with GILT and tested for cytokine profiles, angiogenic and tumorigenic factors, and immune inhibitory molecules in these cells. Data suggests that GILT has an important role in the cytokine profile of melanoma cells. My study also suggests that GILT has an important role in the cytokine profile of melanoma cells. My study also suggests that GILT expression reduces angiogenic molecules such as IL-8 and VEG-F in melanoma cells. Mechanistic studies revealed that GILT insertion also reduced tumorigenic molecule paired box-3 protein (PAX-3) through the colocalization of these molecules. These data suggest that GILT expression plays multiple roles in altering melanoma pathology and immune recognition, which may help devise novel chemoimmunotherapeutics against metastatic melanoma. This study also suggests PAX-3 is susceptible to targeting, which could lead to a less metastatic phenotype of these disease.

Rights

All rights reserved. All rights reserved. Copyright is held by the author.

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