Abstract 455: Pro-apoptotic proteins affect survival of tumor-specific low avidity CD8+ T cells in tolerant mice.

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Abstract A major barrier to cancer vaccines as therapy is the many tolerance mechanisms inhibiting the activation of cancer-specific T cells. Higher avidity T cells have been shown to be more strongly affected by tolerance signals leaving the potential for lower avidity T cells to be effective. These signals as well as co-regulatory signals strongly affect T cell activation, function, and survival in vivo. Our study aims to identify tolerance mechanisms and co-regulatory signals in lower avidity CD8+ T cells as compared to other cells within a T cell repertoire specific for the same cancer antigen. We used the HER-2/neu (neu-N) transgenic mouse model of spontaneous mammary tumors. Vaccines targeted at the HER-2/neu protein induce T cell responses of differing avidities against the immunodominant epitope RNEU420-429. We created high and low avidity TCR transgenic mice whose high and low avidity tumor-specific T cells can be tracked in the tolerized HER-2/neu mice in vivo. T cells from the high and low avidity TCR transgenic mice were adoptively transferred into neu-N mice under different treatment conditions to evaluate changes in protein expression. Treatment groups included: tumor alone, tumor plus a GM-CSF secreting whole cell vaccine, and tumor plus vaccine plus the T regulatory cell (Treg) depleting agent cyclophosphamide. The combination of the Treg depleting agent and vaccine allows the activation of high avidity T cells including the ability of those T cells to reject tumor. Low avidity T cells do not reject tumor with any of these treatments. We used microarrays to compare gene expression between the high and low avidity T cells in tolerant and non-tolerant environments and found several genes with higher expression in the low avidity Tcells. In particular, cell death pathways were upregulated in the low avidity T cells when compared with high avidity T cells in a tolerant environment. The specific molecules within the cell death pathways that showed the most distinction were CD24, FasL, and DR5. Further analysis confirmed that protein expression of these molecules was also increased on low avidity T cells. We also found that these molecules are more highly expressed on T cells undergoing apoptosis. The increases in proteins involved the cell death pathway on low avidity T cells correlates with our finding that in tolerant mice lower avidity T cells have a shorter survival than higher avidity T cells. These studies also show that T cells expressing these death proteins secrete less effector cytokines, including IFNγ, than T cells that do not express them. Currently these proteins are being targeted therapeutically to determine if the survival and function of low avidity T cells can be altered. Thus, this study should identify novel combinatorial immune-based treatments to enhance the overall anti-tumor activity of cancer vaccines. Citation Format: Chelsea M. Black, Elizabeth M. Jaffee, Todd D. Armstrong. Pro-apoptotic proteins affect survival of tumor-specific low avidity CD8+ T cells in tolerant mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 455. doi:10.1158/1538-7445.AM2013-455