TUMOR APOPTOSIS AS MAJOR DETERMINANT OF IMMUNOGENICITY

描述(申请人提供)：细胞介导的免疫具有重要的 在预防和治疗癌症方面的作用。然而，其免疫原性较差。 肿瘤细胞常常阻止形成有效的抗肿瘤免疫。 回应。最近的数据有力地表明，肿瘤起源的表现 树突状细胞(DC)的抗原是诱导移植物抗宿主病的必要步骤。 对肿瘤的免疫反应。重要的是，大量的凋亡细胞可以 DC的触发成熟和来源的抗原的呈递 凋亡性细胞。因此，诱导肿瘤细胞凋亡也可能 提高肿瘤免疫原性。这些研究将检验这一假设 超过一定阈值的凋亡肿瘤细胞的积累是至关重要的 诱导保护性肿瘤特异性免疫的因素。至 完成这项工作，我们将建立体内肿瘤模型，其中肿瘤 可在原位诱导细胞凋亡。因此，肿瘤细胞系将在 Fas介导的细胞凋亡是通过一种混合蛋白来诱导的 他莫昔芬。保护性肿瘤特异性免疫反应的开发将是 通过过继转移荷瘤小鼠的淋巴细胞进行监测，这 用他莫昔芬治疗，进入继发性免疫缺陷宿主后 挑战亲代肿瘤细胞。DC在AN开发中的作用 对凋亡的肿瘤细胞的免疫反应将通过使用两个 战略。第一个将使用具有选择性表达的转基因小鼠 树突状细胞或巨噬细胞中的自杀基因。有条件地消融DC(或 巨噬细胞)将显示这些细胞是否对 对凋亡的肿瘤细胞的免疫反应的发展。第二 该策略将使用TAP-1缺陷小鼠，在这些小鼠中，DC或巨噬细胞只能 MHC-I类途径中存在的抗原是由于选择性表达 点击-1。来自这些小鼠的抗原提呈细胞将被测试其 呈现来自于凋亡的肿瘤细胞的抗原的能力。这些 研究将为进一步的临床前和临床研究提供基础 检测细胞凋亡水平是否能促进抗肿瘤免疫 化疗和放射治疗所致。

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.