Date of Award

Spring 2003

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Committee Director

Richard P. Ciavarra

Committee Member

Stephen J. Beebe

Committee Member

William F. Glass

Committee Member

Kenneth D. Somers

Committee Member

George L. Wright, Jr.

Abstract

Prostate cancer is the most common form of non-cutaneous cancer among men in the United States and the second most common cause of cancer-related death among men with approximately 189,000 new cases diagnosed and 30,200 deaths of the disease in 2002. Prostate cancer can be a treatable disease but once it becomes metastatic there are no acceptable therapies. For this reason, immunotherapy has been attempted but the results have been disappointing. The TRAMP model was used to evaluate specific interactions between an intact murine immune system and a prostate tumor that expressed a naturally processed weak tumor antigen. Vaccination trials for cancer patients have detected tumor-specific immune cells in the peripheral lymphoid organs such as blood, even with progressing disease. This observation prompted us to hypothesize that factors within the tumor microenvironment disable the immune response. The first studies characterized the cellular infiltrate of TRAMP tumors. Then the expression of signal transducing molecules of infiltrating T cells was analyzed in vivo and an in vitro co-culture assay system examined the role of common tumor-infiltrating myeloid subsets in the alterations to T cells. These studies demonstrated that TRAMP tumors were unexpectedly rich in host myeloid cells and that expression of components of the CD3/TCR complex was decreased on infiltrating T cells. Unexpectedly, these studies determined that as many as 30% of infiltrating T cells expressed the γ/δ TCR complex, a very rare T cell subset with an unknown roe in tumor surveillance and rejection. Additionally, tetramers specific for the tumor antigen WT-1 identified tumor specific T cells and showed that these cells were more normal in their expression of signal transducing molecules. Finally, using in vitro co-culture assays it was determined that GR1 positive cells mediated the loss of signal transducing molecules and that H2O2 generated by these cells mediated the loss of the TCR-ζ chain in infiltrating T cells. These results show for the first time, that some of the same mechanisms that suppress immune function in chronic inflammation also suppress immune function of infiltrating T cells.

Comments

Dissertation submitted to the Faculty of Eastern Virginia Medical School and Old Dominion University in Partial Fulfillment of the Requirement for the Degree of Doctor of Philosophy in Biomedical Sciences.

DOI

10.25777/etwb-a036

ISBN

9780496385324

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