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（由申请人提供）：该建议是研究NKG2D免疫受体在对肿瘤细胞的免疫反应中的功能。 NKG2D是由所有天然杀伤（NK）细胞表达的刺激受体，所有活化的细胞毒性T细胞（CTL），所有活化的巨噬细胞以及γ/Delta T细胞和NK1.1+ T细胞的分数。 NKG2D识别包括RAEL和H60在内的几种相关细胞表面蛋白（配体）。靶细胞对高水平的NKG2D配体的表达会导致NK细胞和活化的巨噬细胞的强烈攻击，以及CTL对肿瘤特异性抗原的反应增强。大多数正常细胞不表达这些NKG2D配体。相比之下，大多数肿瘤细胞系都会上调RAEL和其他NKG2D配体。要检验的假设是NKG2D及其配体代表了肿瘤免疫监视的系统。也就是说，建议NKG2D配体通常在发育中的肿瘤细胞中上调，作为警告和激活免疫系统的一种手段，并且由此产生的免疫反应有助于限制正常动物中肿瘤的发育和/或生长。该假设将使用几种方法进行检验。此外，初步实验表明，转导向高水平的NKG2D配体转导的肿瘤细胞系在辐照时充当有效的治疗性癌症疫苗，可刺激针对相同类型的已建立肿瘤的有效免疫反应（但未被转导）。因此，将进行研究，以确定这种方法的有效性以及是否可以有效地与其他免疫疗法相结合。具体目标1：确定与不同衔接子分子相关的NKG2D同工型在刺激和刺激NKG2D+细胞中的作用。特定目标2：生成和表征缺乏NKG2D表达的靶向小鼠。特定目的3：评估NKG2D在体内肿瘤监测中的重要性。特定目标4：确定NKG2D刺激的功效作为癌症免疫疗法