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Modulation of T Cell Tolerance in a Murine Model for Immunotheraphy of Prostatic Adenocarcinoma

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Final rept. 1 Sep 2001-31 Aug 2006

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The goal of this project is to characterize T cell tolerance to prostate tumor antigens and to 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 final summary we report that subsequent to adoptive transfer of nave TAg-specific T cells into TRAMP mice there is rapid expansion and contraction of the tumor-specific T cells followed by accumulation of a population of T cells that persist in the prostate as tolerant and suppressive. Co-transfer of TAg-specific 0D4 T cells partially rescues the tolerant suppressive phenotype of prostate-tumor-specific T cells although over time tolerance of the CD8 T cells ensues. In contrast transfer of CD4 T cells does not reverse tolerance of the previously-tolerized 0D8 cells. The suppressive nature of these CD8 T cells was also studied and we present preliminary data on the characterization of these novel suppressor cells. These data demonstrate the critical balance between T cell activation and tolerance and support a mechanism by which tumor growth may induce tolerance and suppressor activity in T cells previously primed to tumor-specific antigens. A greater understanding of how tolerance of these tumor specific T cells can be reversed willcertainly lead to more potent anti-tumor immunotherapies.

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  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research

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