Notch-1 in T Cells: a central mediator of tumor induced anergy

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DESCRIPTION (provided by applicant): Myeloid-derived suppressor cells (MDSC) impair T cell function in tumor-bearing hosts through one or more processes, including the depletion of the amino acids arginine and cysteine, the release of reactive oxygen species and nitric oxide, and the induction of regulatory T cells. However, the molecular mechanisms by which T cells become dysfunctional after contact with MDSC remain unclear. Notch homolog 1-translocation-related protein (Notch-1) has been determined to be an important signal transduction molecule in the promotion of acute lymphoblastic T cell leukemia. However, its influence on normal T cell responses is poorly understood. The proposed study will be the first to determine the significance of the inhibition of Notch-1 in T lymphocytes in the MDSC-induced T cell suppression occurring in solid tumors. Further, through the use of novel antigen- specific transgenic murine models, this investigation will advance the understanding of the role of Notch-1 in normal T cell proliferation, cytotoxicity, and cytokine production. In preliminary studies, tumor-infiltrating MDSC expressing arginase I inhibited the expression of Notch-1 in activated T cells at the same ratios at which they blocked T cell proliferation. In addition, activated T cells cultured with inhibitors of Notch-1 cleavage displayed decreased cell proliferation and impaired production of interferon gamma (IFN?). These results were confirmed in cells from Notch-1 conditional knockout mice, in which proliferation of activated T cells also decreased. The preliminary data suggest that Notch-1 plays a significant role in normal T cell function and that a decrease in T cell-Notch-1 expression is a possible mechanism for the MDSC-induced T cell inhibition in tumors. Thus, we hypothesize that MDSC induced in solid tumors inhibit the expression of Notch-1 in T cells and thereby impair the development of a protective anti-tumor T cell response. The completion of this research is expected to provide mechanistic insights into the suppression of T cells by MDSC in cancer. This study may also enable the design of new therapeutic approaches to reverse T cell tolerance in cancer or other conditions such as autoimmune diseases, chronic infections, and trauma, which are characterized by the accumulation of MDSC. To test our hypothesis and to achieve the objectives of this project, we propose the following Specific Aims: Specific Aim 1: Test the prediction that arginase I-expressing MDSC inhibit T cell function in vitro by impairing the expression of Notch-1. Specific Aim 2: Determine in vivo the role of Notch-1 in the T cell suppression induced by tumor-infiltrating MDSC.