Following vaccination of patients with an ovarian tumor-associated-antigen, tumor-specific T cells are found in the peripheral blood that are fully responsive to activation via their T cell receptor (TCR). However, T cells (both CD4+ and CD8+) derived from the microenvironment of the ovarian tumors are either hyporesponsive or nonresponsive to the same TCR stimulation used for peripheral blood T cells. The hyporesponsiveness of the tumor-associated T cells is due in part to an arrest in the TCR signaling cascade, and is reversible both in vitro and in vivo by IL-12. While the fate of human T cells following their entry into the tumor microenvironment has not yet been determined we predict and will test the possibility that functional T cells, upon entry into the tumor, incur an arrest in the TCR signaling cascade rendering these cells anergic. Because stromal fibroblasts represent such a major cell type within the tumor microenvironment, and because they express biologically active cytokines and co-inhibitory surface bound molecules, our focus will be upon the role of these cells in modulating lymphocyte function and survival. This is to be addressed first in vitro by co-cultivating tumor-specific T cells derived from the peripheral blood with autologous fibroblasts derived from the tumor and comparing T cell survival, T cell activation potential, and changes in the expression and phosphorylation patterns of the signaling molecules following a TCR stimulation to T cells cultivated without fibroblasts.
In Aims 1 and 2, the soluble and membrane bound biologically active factors produced or expressed by fibroblasts, lymphocytes, dendritic cells or tumor cells that contribute to the TCR signaling arrest, and to the prolonged survival of the tumor-associated memory T cells are to be identified. In view of the recognized heterogeneity of fibroblasts and their demonstrated pleiotropic effects on T cells, the possibility that phenotypically distinct subsets of fibroblasts exist, and are responsible for the enhanced survival of T cells, the arrest of T cell signaling, and the enhancement of tumor growth is to be addressed in Aim 3. In the final Aim, a test is made of the therapeutic efficacy of strategies designed to prevent or reverse the inhibitory TCR signaling arrest, to enhance the survival of tumor-associated memory T cells, and to retard tumor progression. This last aim is achieved using function blocking antibodies in a xenograft model in which tumor cells, T lymphocytes and fibroblasts are implanted into NOD-scid/IL-2 receptor ? chainnull (NSG) mice. This model has made it possible for the first time to monitor the effect of human fibroblasts and other stromal cells on tumor growth, and T cell function for prolonged periods in vivo. Using this model the possible beneficial effects of enhancing the survival and preventing or reversing the TCR arrest in tumor-associated T cells upon the control of tumor progression will be determined. These studies are expected to provide a basis for the design of new strategies that could be used to enhance the therapeutic effectiveness of current cancer vaccines.
Cancer vaccines induce tumor-specific T cells that circulate in the peripheral blood, but when these T cells leave the circulation and enter the tumor they fail to attack and kill tumor cells. We intend to determine what is responsible for the apparent functional arrest of the tumor-specific T cells and to design and test ways to prevent and/or reverse the shutdown of these cells once they reach the tumor.
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