Characterization of Mouse Prostate Tumor-Infiltrating Leukocytes

<p>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 <em>in vivo</em> and an <em>in vitro</em> 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 <em>in vitro</em> 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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Year dc:date.available

2003

Author dc:creator

• Holterman, Daniel Alan

Contributors dc:contributor

• Richard P. Ciavarra
• Stephen J. Beebe
• William F. Glass
• Kenneth D. Somers
• George L. Wright, Jr.

• Immune response
• Leukocytes
• Prostate tumor-infiltrating
• T cell receptors
• Immunology and Infectious Disease
• Oncology

Identifier

9780496385324

OAI identifier oai:identifier

oai:digitalcommons.odu.edu:biomedicalsciences_etds-1040