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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
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National Cancer Institute Division of Basic Sciences
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Zhu, Ziqiang; Cuss, Steven M; Singh, Vinod et al. (2015) CD4+ T Cell Help Selectively Enhances High-Avidity Tumor Antigen-Specific CD8+ T Cells. J Immunol 195:3482-9
Shurin, Michael R; Umansky, Viktor; Malyguine, Anatoli et al. (2014) Cellular and molecular pathways in the tumor immunoenvironment: 3rd Cancer Immunotherapy and Immunomonitoring (CITIM) meeting, 22-25 April 2013, Krakow, Poland. Cancer Immunol Immunother 63:73-80
Hudson, R S; Yi, M; Esposito, D et al. (2013) MicroRNA-106b-25 cluster expression is associated with early disease recurrence and targets caspase-7 and focal adhesion in human prostate cancer. Oncogene 32:4139-47
Hurwitz, Arthur A; Watkins, Stephanie K (2012) Immune suppression in the tumor microenvironment: a role for dendritic cell-mediated tolerization of T cells. Cancer Immunol Immunother 61:289-93
Watkins, Stephanie K; Hurwitz, Arthur A (2012) FOXO3: A master switch for regulating tolerance and immunity in dendritic cells. Oncoimmunology 1:252-254
Watkins, Stephanie K; Zhu, Ziqiang; Watkins, Keith E et al. (2012) Isolation of immune cells from primary tumors. J Vis Exp :e3952
Watkins, Stephanie K; Zhu, Ziqiang; Riboldi, Elena et al. (2011) FOXO3 programs tumor-associated DCs to become tolerogenic in human and murine prostate cancer. J Clin Invest 121:1361-72
Chen, Xin; Hamano, Ryoko; Subleski, Jeffrey J et al. (2010) Expression of costimulatory TNFR2 induces resistance of CD4+FoxP3- conventional T cells to suppression by CD4+FoxP3+ regulatory T cells. J Immunol 185:174-82
Shafer-Weaver, Kimberly A; Watkins, Stephanie K; Anderson, Michael J et al. (2009) Immunity to murine prostatic tumors: continuous provision of T-cell help prevents CD8 T-cell tolerance and activates tumor-infiltrating dendritic cells. Cancer Res 69:6256-64
Shafer-Weaver, Kimberly A; Anderson, Michael J; Stagliano, Katherine et al. (2009) Cutting Edge: Tumor-specific CD8+ T cells infiltrating prostatic tumors are induced to become suppressor cells. J Immunol 183:4848-52

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