Pilot Project #2

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Project Summary: Prostate cancer (PCa) is the most common non-skin malignancy and the cancer second most responsible for death in men in United States. Prior studies with animal models of PCa and with humans demonstrated that the prostate produces various growth factors. Addition or blocking of these factors alters PCa cell proliferation and other functions. Among these factors, transforming growth factor-β1 (TGF-β) is involved in tumorigenicity, displays potent immunosuppressive activities, and is required for the conversion of conventional CD4+ T cells to FoxP3+ regulatory T (TR) cells. TR cells that express the transcription factor Foxp3 are essential for normal immune function; absence of TR cells results in multi-organ autoimmunity and death. A clear role of TGF-β and its effect on TR during PCa development and progression lacks experimental evidence. In this proposal, we plan to investigate the underlying mechanisms involved in the context of TGF-β and/or TR using PCa cell lines, derived from transgenic mouse for prostate cancer (TRAMP), in C57/B6 mice. Of these cell lines, TRAMP- C1 and TRAMP-C2 form tumors; TRAMP-C3 fails to do so. These mouse cell lines of PCa can be used to obtain the long-term goal of this project, which is to address the fundamental question: Do TR cells and/or TGF-β levels relate to differences in tumorigenicity of the TRAMP cell lines (C1, C2, and C3)? The objective of this project is to define the role of TGF-β production by host cells in response to or TGF-β expression by TRAMP cell lines and to establish the function of TGF-β on the conversion of naive CD4+ T cells into Foxp3-expressing TR cells.