TUMOR APOPTOSIS AS MAJOR DETERMINANT OF IMMUNOGENICITY

描述（由申请人提供）：细胞介导免疫具有重要的

DESCRIPTION (provided by applicant): Cell-mediated immunity has an important role in prevention and treatment of cancer. However, poor immunogenicity of tumor cells often prevents development of an effective anti-tumor immune response. Recent data strongly suggest that presentation of tumor-derived antigens by dendritic cells (DC) is a necessary step in the induction of an immune response to the tumor. Importantly, abundance of apoptotic cells can trigger maturation of DC and presentation of antigens derived from the apoptotic cells. Therefore, induction of tumor cell apoptosis may also improve tumor immunogenicity. These studies will test the hypothesis that accumulation of apoptotic tumor cells above a certain threshold is a crucial factor leading to the induction of a protective tumor-specific immunity. To accomplish this, we will establish an in vivo tumor model wherein tumor apoptosis can be induced in situ. Thus, tumor cell lines will be generated in which Fas-mediated apoptosis is induced via a hybrid protein responsive to tamoxifen. Development of a protective tumor-specific immune response will be monitored by adoptive transfer of lymphocytes from tumor-bearing mice, which were treated with tamoxifen, into secondary immunodeficient hosts followed by challenge with parental tumor cells. The role of DC in development of an immune response to apoptotic tumor cells will be determined by using two strategies. The first will employ transgenic mice with selective expression of a suicide gene in DC or macrophages. Conditional ablation of DC (or macrophages) in these mice will show whether these cells are essential for the development of an immune response to apoptotic tumor cells. The second strategy will employ TAP-1-deficient mice in which DC or macrophages only can present antigens in the MHC class I pathway because of selective expression of TAP-1. Antigen-presenting cells from these mice will be tested for their abilities to present antigens derived from apoptotic tumor cells. These studies will provide the basis for further pre-clinical and clinical studies testing whether levels of apoptosis promoting anti-tumor immunity can be induced by chemotherapy and irradiation.