Modulation of T Cell Tolerance in a Murine Model for Immunotherapy of Prostatic Adenocarcinoma
Annual rept. 1 Sep 2003-31 Aug 2004
STATE UNIV OF NEW YORK UPSTATE MEDICAL CENTER SYRACUSE
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The goal of this project is to characterize T cell tolerance to prostate tumor antigens and identify the role of costimulatory receptors in overcoming this tolerance. Identification of these processes will assist in the development of novel therapeutic approaches for treating prostate cancer. We use the TRAMP model, a transgenic mouse line that develops primary prostatic tumors due to expression of the SV4O T antigen TAg under the transcriptional control of a prostate-specific promoter. In this summary, we report that adoptive transfer of naive TAg-specific T cells into TRAMP mice results in an initial proliferative expansion followed by a clonal deletion within 5 days. Vaccination of mice with dendritic cells pulsed with the cognate antigen results in expansion in the peripheral lymphoid compartments and subsequent trafficking to the Prostate-draining lymph nodes pDLN. However, 11 days post-vaccine, Ag-specific T cells were no longer detectable in pDLN. In contrast, a large percentage of Ag-specific T cells were still present in the prostatic tissue of vaccinated TRAMP mice, and persisted for at least 21 days. These data demonstrate that an Ag-pulsed DC vaccine may rescue prostate-specific T cells from peripheral tolerance in tumor-bearing mice and promote their infiltration and survival in the prostate. On going studies are testing the role of CTLA-4 blockade and CD4 T cell help to rescue this deletion.
- Anatomy and Physiology
- Medicine and Medical Research