Tumor Growth and Microenvironment Influence T Cell Tolerance to Tumor Antigens

Division Of Basic Sciences - Nci

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Abstract

The goal of this project is to test the hypothesis that the tumor microenvironment plays a critical role in 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 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 and in a report published last year, we demonstrated that transfer of CD8+ MHC class I-restricted T cells into TRAMP mice resulted in an initial proliferative expansion followed by deletion from the peripheral lymphoid organs, but retention of a subset of T cells in the prostate, the site of tumor formation; these residual tumor-specific T cells become unresponsive to antigenic stimulation (ie, they are tolerant). In addition,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 suppressor cells have the capacity to suppress proliferation of other T cells. However, vaccination of mice with a dendritic cell vaccine caused an increase in the accumulation of T cells in the prostate and retention of reactivity to antigen, associated with a decrease in prostate weight. More recently,we have observed 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, the laboratory has also observed 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 help prevents T cell tolerance and reduces tumor growth. This work has been prepared for submission as a new manuscript. Naturally-occurring regulatory T (Treg) cells are a population of suppressive lymphocytes that control autoreactivity and regulate immunity. In a related study, we examined the effect if IL-2 family cytokines on Treg cell activity. We reported that IL-2 activated STAT5, induced Treg cell activation and proliferation. We observed that IL-7 and IL-15 induced STAT5 phosphorylation, which correlated with enhanced viability. However, only in the presence of IL-2 did Tregs acquire potent suppressor function. This finding is surprising, as IL-15 as well as IL-2 use the same IL-2R beta and gamma chains for signaling. In contrast, IL-21 activated STAT3 but did not activate STAT5 and had no effect on Treg viability, activation, or function. These findings are critical for the on-going development of clinical protocols that employ these cytokines as adjuvants for immunotherapy, as any cytokines which inadvertently activate Treg cells may be counter-productive for approaches that seek to enhance tumor immunity. 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 which exist in both normal and transformed prostate tissues. Interestingly, the dendritic cells isolated from the TRAMP prostate are incapable of stimulating naive T cell proliferation, whereas dendritic cells from normal prostate tissues are stimulatory. However, 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.