The goal of this project is to test the hypothesis that the tumor microenvironment plays a critical role in influencing T cell responses to tumor antigens. This microenvironment is comprised of a complex interaction between tumor cells, lymphocytes, myeloid cells, and stromal cells. This project uses TRAMP mice which express the transforming SV40 TAg under the transcriptional control of a prostate-specific promoter, which causes the development of murine prostate cancer. TAg-specific T cells are adoptively transferred into TRAMP mice. We previously reported that CD8+ T cells become tolerized when they enter the tumor microenvironment. In a report recently submitted for publication, we identified these tolerant, tumor-specific CD8+ T cells as regulatory, or suppressor, T cells, and induction of suppressor activity is dependent on infiltration into the prostate. These regulatory cells have the capacity to suppress proliferation of other T cells. We recently reported that transfer of TAg-specific CD4+ T cells also undergo transient activation before deletion and trafficking to the prostate. Taking advantage of this transient activation, we further demonstrated that co-transfer of both CD4+ and CD8+ T cells delays tolerization of the CD8+ T cells. Continuous administration of the tumor-specific CD4+ T cell prevented T cell tolerance and reduced tumor growth. Our current work is aimed at understanding the mechanism by which T cells become tolerized in the tumor micro-environment. We have identified a population of dendritic cells (DCs) which exist in both normal and transformed prostate tissues. Interestingly, the dendritic cells isolated from the TRAMP prostate are incapable of stimulating proliferation of nave T cell proliferation in vitro, whereas dendritic cells from normal prostate tissues are stimulatory. Further examination of the T cells primed by the tumor-infiltrating DC (TiDC) reveal that they are tolerized and have suppressor function. These findings imply that these TiDC contribute to the tolerization of tumor-specific T cells in vivo, as well. Our early studies suggest that depletion of the TiDC, using antibodies that recognize the BST-2 antigen expressed on their surface, prevents tolerization of the T cells. Interstingly, dendritic cells isolated from TRAMP prostates following transfer of tumor-specific CD4+ T cells do stimulate naive T cells, suggesting that the CD4+ T cells alter the tumor micro-environment and empower the DC to sustain T cell responses. We are currently examining the role of multiple suppressive mechanisms that the TRAMP tumor-resident dendritic cells may use to restrict T cell-mediated anti-tumor immune responses.
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