Z01 BC 010563 (Z01) | |||
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Title | Modulating T cell tolerance to elicit tumor immunity and autoimmunity | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Hurwitz, Arthur | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $363,861 | Project Dates | 10/01/2004 - N/A |
Fiscal Year | 2007 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Autoimmune Diseases (50.0%) |
Melanoma (30.0%) Prostate (40.0%) Urinary System (40.0%) |
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Research Type | |||
Vaccines Systemic Therapies - Discovery and Development |
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Abstract | |||
The goal of this laboratory is to study how T cells respond to self-antigens in the context of tumor immunity and autoimmune disease. As they mature in the thymus, most high avidity self-reactive T cells are deleted, although a small fraction of self-reactive T cells escape this negative selection and emigrate to the periphery. These residual cells remain tolerant of self-antigen in the absence of abnormal stimuli. However, under certain circumstances, they may become activated to cause pathologic responses. By understanding how T cells become activated and what regulates their tolerant state, we plan to utilize this knowledge to elicit potent anti-tumor responses and to define novel approaches to treating autoimmune disease. There are 2 on-going sub-projects. The first project is a melanoma-related project that is examining tolerance to a pigmentation antigen, TRP-2, which is co-expressed by both melanoma cells as well as their non-transformed counterparts, melanocytes. We have created 3 transgenic mouse lines that bear rearranged TcR genes which differ in their functional avidity for TRP-2. We characterized the first line, which is intermediate in avidity. T cells from these mice mature in both wild-type and TRP-2-deficient mice and maintain antigen specificity and responsiveness, as measured in vitro. However, even in the presence of TRP-2 expressing tumor, there is no evidence for T cell responses in vivo, suggesting "ignorance" of the antigen. However, when primed with a TRP-2 vaccine, the T cells do become activated and traffic to the tumor, but are not tolerized. Our on-going studies will examine the reactivity of low and high avidity T cells and test their ability to mediate tumor immunity and autoimmune vitiligo. The second project involves studying T cell reactivity to tumor antigens using a murine model of prostate cancer. In the ?TRAMP? model, mice develop primary prostatic tumors as a result of transgenic expression of the SV40 T antigen (TAg) under the control of a prostate-specific promoter. In our studies, TRAMP mice are adoptively transferred with T cells derived from TcR transgenic mice that have specificity for either an MHC class I- or class II-restricted epitope of TAg. We recently reported that transfer of the class I-restricted T cells into TRAMP mice results in an initial proliferative expansion followed by deletion from the peripheral lymphoid organs, but retention in the prostate, the site of tumor formation. These T cells are unresponsive to antigenic stimulation. However, vaccination of mice with a dendritic cell vaccine causes an increase in the accumulation of T cells in the prostate and retention of reactivity, associated with a decrease in prostate weight, a measure of tumor size. Our more recent data demonstrate that tumor-specific CD4+ T cells also undergo a similar, but slower tolerization. However, co-transfer of these cells can delay tolerization of the CD8+ tumor-specific T cells. On-going studies are determining gene expression profiles of T cells following anergy induction as well as characterization of signals that recruit T cells to the prostate. Finally, we have observed that TAg-specific T cells from TRAMP mice function as regulatory or suppressor T cells. Our on-going studies will examine the mechanisms by which T cells are tolerized in the TRAMP model and also the mechanisms which regulate trafficking of tumor-specifc T cells to the prostate. |