Date of Award

2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

Azizul Haque

Abstract

Melanoma is an aggressive skin cancer that plagues Western populations. Current treatments such as surgery, chemotherapy, and high-dose radiation have had some success, but often fail in treating late stage metastatic melanoma. Immunotherapies have been successful in treating a small percentage of late stage patients, but these treatments do not provide a long-lasting response to effectively clear the tumor. Therefore, current studies have been investigating whether combining common treatments with immunotherapies would provide the necessary boost to further improve tumor killing. An optimum presentation of HLA class II proteins is essential for the activation of CD4+ T cells, which provide a sustained killing of malignant tumors by activating cytotoxic CD8+ T cells. Our laboratory has recently shown that the induction of Gamma-Interferon-inducible Lysosomal Thiol reductase (GILT) in melanoma favors HLA class II antigen processing and CD4+ T cells recognition of tumors. The present study examined the role of GILT in generating a greater pool of reduced and functional epitopes for HLA class II-mediated presentation and recognition of CD4+ T cells. This study also investigated the mechanisms by which GILT expression negatively regulates a tumorigenic molecule, paired box 3 (PAX3), in melanoma cells; and how regulation of PAX3 leads to melanoma cell sensitization to radiation and chemoimmunotherapy. Additionally, this study tested a chemotherapeutic agent (GA-DM), which induced apoptosis in a p53-dependent pathway and altered GILT, PAX3, and HLA class II molecules in melanoma cells in vitro. Interestingly, the combination of radiation and GA-DM treatment in vivo in the B16 melanoma mouse model displayed increased survival and decreased tumor volume among treatment groups. Based upon the results of this study, the combination treatment of radiation and GA-DM could be utilized to eliminate melanoma cells while boosting immune responses in the host. Understanding the molecular mechanisms of GILT-mediated downregulation of PAX3 as well as the radiation and GA-DM treatment death pathway could lead to a new target for devising novel chemoimmunotherapeutics for late stage metastatic melanoma.

Rights

All rights reserved. Copyright is held by the author.

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