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

描述（由申请人提供）：髓源性抑制细胞（MDSC）通过一个或多个过程损害肿瘤宿主的T细胞功能，包括氨基酸精氨酸和半胱氨酸的消耗，活性氧和一氧化氮的释放，以及调节性T细胞的诱导。然而，T细胞与MDSC接触后功能失调的分子机制尚不清楚。Notch同源1易位相关蛋白（Notch-1）已被确定为促进急性淋巴细胞T细胞白血病的重要信号转导分子。然而，其对正常T细胞反应的影响尚不清楚。这项拟议的研究将首次确定T淋巴细胞中Notch-1的抑制在mdsc诱导的实体瘤中发生的T细胞抑制中的意义。此外，通过使用新的抗原特异性转基因小鼠模型，本研究将促进对Notch-1在正常T细胞增殖、细胞毒性和细胞因子产生中的作用的理解。在初步研究中，表达精氨酸酶I的肿瘤浸润性MDSC在激活的T细胞中抑制Notch-1的表达，其比例与阻断T细胞增殖的比例相同。此外，激活T细胞

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. PUBLIC HEALTH RELEVANCE: This study will determine the role of Notch homolog 1-translocation-related protein (Notch-1) in the T cell suppression induced by myeloid-derived suppressor cells (MDSC) in tumors. Information garnered from this effort is expected to provide insights into the mechanisms underlying T cell suppression in cancer, which may enable the design of new therapeutic approaches to prevent and/or reverse T cell tolerance in tumors. These approaches may also benefit patients suffering from other conditions such as autoimmunity diseases, chronic infections, and trauma, which are also characterized by the accumulation of MDSC.