In order to generate and monitor effective and specific immune responses against tumors, a clear understanding of relevant tumor antigens and their derivative epitopes recognized by T lymphocytes is warranted. The characterization of tumor antigen epitopes recognized by T lymphocytes has been a major focus of study over the past decade. Both CD8+ and CD4+ T lymphocytes contribute to the immune response against tumors, and the determination of the epitopes they recognize is necessary for their incorporation into immunotherapy protocols for cancer. The tumor antigens recognized by T lymphocytes fall into 3 major categories: Tumor-specific (TSA), Cancer Testis (CT), and Tumor Associated Antigens (TAA). Our goal in the following studies was to characterize a novel TAA, EphA2, since this protein has been linked to metastasis in numerous cancer settings.
The definition of epitopes seen by T lymphocytes will assist in vaccine strategies for immunotherapy protocols against EphA2+ tumors. In the following studies, I have defined 8 novel EphA2 T cell epitopes (5 HLA-A2 restricted and 3 HLA-DR4 restricted) recognized by CD8+ and CD4+ T lymphocytes, respectively. The anti-EphA2 CD4+ functional response was skewed based on the presence of disease or increased staging of RCC disease, with patients with active disease exhibiting a Th2-biased CD4+ response. I have also linked the expression of EphA2 in primary RCC tumors to the time to recurrence in patients affected with RCC. Furthermore, I have demonstrated that the cell surface expression of EphA2 on tumors can be modulated using EphA2 agonists. This agonist treatment results in the enhanced recognition of EphA2+ tumors by specific CTLs. With reports of the overexpression of protein phosphatases (PPs) in several cancer settings, we discovered the EphA2 was constitutively underphosphorylated in certain cancer cell lines, likely as the consequence of overexpressed PP activity. Finally, I have shown that by neutralizing the activity of cellular phosphatases utilizing phosphatase inhibitors, that we can induce the phosphorylation of EphA2 and its subsequent degradation via a largely proteasome-dependent pathway. As a result, this thesis has defined a novel tumor antigen, EphA2, and demonstrated the possibility that modulation of its expression in tumor cells may result in increased recognition by specific T effector cells that may be germane to the design of improved and efficacious therapies for the treatment of patients with EphA2+ tumors.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-07122004-132808 |
| Date | 06 August 2004 |
| Creators | Herrem, Christopher John |
| Contributors | Theresa Whiteside, Ph.D., Thomas Smithgall, Ph.D., Russell Salter, Ph.D., Walter Storkus, Ph.D., William Chambers, Ph.D. |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-07122004-132808/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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