Role of NKG2D in immune responses to tumors

NKG2D 在肿瘤免疫反应中的作用

• 批准号: 6575797
• 负责人: DAVID H RAULET
• 金额: $ 26.78万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-31 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6575797
• 关键词: binding proteins; gene targeting; genetically modified animals; immunologic receptors; laboratory mouse; neoplasm /cancer immunology; neoplasm /cancer vaccine; protein isoforms; receptor expression; vaccine development

DESCRIPTION (provided by applicant): The proposal is to investigate the function of the NKG2D immunoreceptor in immune responses to tumor cells. NKG2D is a stimulatory receptor expressed by all natural killer (NK) cells, all activated cytotoxic T cells (CTL), all activated macrophages, and fractions of gamma/delta T cells and NK1.1+ T cells. NKG2D recognizes several related cell surface proteins (ligands), including Rael and H60. Expression of high levels of NKG2D ligands by target cells results in a strong attack by NK cells and activated macrophages, and an enhanced response of CTL to tumor-specific antigens. Most normal cells do not express these NKG2D ligands. Most tumor cell lines, in contrast, upregulate Rael and other NKG2D ligands. The hypothesis to be tested is that NKG2D and its ligands represent a system for tumor immunosurveillance. That is, it is proposed that NKG2D ligands are normally upregulated in developing tumor cells as a means to alert and activate the immune system, and that the resulting immune response serves to limit the development and/or growth of tumors in normal animals. This hypothesis will be tested using several approaches. In addition, preliminary experiments demonstrate that tumor cell lines transduced to express high levels of NKG2D ligands, when irradiated, function as potent therapeutic cancer vaccines that stimulate an effective immune response against established tumors of the same type (but not transduced). Therefore, studies will be undertaken to establish how effective this approach is and whether it can be effectively combined with other immunotherapies. Specific Aim 1: To determine the role of NKG2D isoforms associated with different adapter molecules in stimulating and costimulating NKG2D+ cells. Specific Aim 2: To generate and characterize gone targeted mice lacking NKG2D expression. Specific Aim 3: To assess the importance of NKG2D in surveillance of tumors in vivo. Specific Aim 4: To determine the efficacy of NKG2D stimulation as a cancer immunotherapy

描述（申请人提供）：该提案旨在研究NKG2D免疫受体在肿瘤细胞免疫反应中的功能。 NKG2D 是一种刺激性受体，由所有自然杀伤 (NK) 细胞、所有活化的细胞毒性 T 细胞 (CTL)、所有活化的巨噬细胞以及部分 γ/δ T 细胞和 NK1.1+ T 细胞表达。 NKG2D 可识别多种相关的细胞表面蛋白（配体），包括 Rael 和 H60。靶细胞表达高水平的 NKG2D 配体，导致 NK 细胞和活化的巨噬细胞强烈攻击，并增强 CTL 对肿瘤特异性抗原的反应。大多数正常细胞不表达这些 NKG2D 配体。相比之下，大多数肿瘤细胞系上调 Rael 和其他 NKG2D 配体。要测试的假设是 NKG2D 及其配体代表肿瘤免疫监视系统。也就是说，提出NKG2D配体在发育中的肿瘤细胞中通常上调，作为警告和激活免疫系统的手段，并且由此产生的免疫反应用于限制正常动物中肿瘤的发育和/或生长。该假设将使用多种方法进行检验。此外，初步实验表明，转导表达高水平 NKG2D 配体的肿瘤细胞系在受到辐射时可作为有效的治疗性癌症疫苗，刺激针对相同类型（但未转导）已建立肿瘤的有效免疫反应。因此，将进行研究以确定这种方法的有效性以及它是否可以与其他免疫疗法有效结合。具体目标 1：确定与不同接头分子相关的 NKG2D 亚型在刺激和共刺激 NKG2D+ 细胞中的作用。具体目标 2：生成并表征缺乏 NKG2D 表达的目标小鼠。具体目标 3：评估 NKG2D 在体内肿瘤监测中的重要性。具体目标 4：确定 NKG2D 刺激作为癌症免疫疗法的功效