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（由申请方提供）：该提案旨在研究NKG 2D免疫受体在肿瘤细胞免疫应答中的功能。NKG 2D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γ/δ T细胞和NK1.1+ T细胞部分表达。NKG 2D识别几种相关的细胞表面蛋白（配体），包括Rael和H60。靶细胞高水平表达NKG 2D配体导致NK细胞和活化巨噬细胞的强烈攻击，以及CTL对肿瘤特异性抗原的增强应答。大多数正常细胞不表达这些NKG 2D配体。相反，大多数肿瘤细胞系上调Rael和其他NKG 2D配体。待检验的假设是NKG 2D及其配体代表肿瘤免疫监视系统。也就是说，提出NKG 2D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手段，并且所产生的免疫应答用于限制正常动物中肿瘤的发育和/或生长。这一假设将使用几种方法进行检验。此外，初步实验表明，经转导以表达高水平NKG 2D配体的肿瘤细胞系在辐照时可作为有效的治疗性癌症疫苗发挥作用，刺激针对相同类型（但未转导）已建立肿瘤的有效免疫应答。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有效地与其他免疫疗法相结合。具体目的1：确定与不同衔接子分子相关的NKG 2D亚型在刺激和共刺激NKG 2D+细胞中的作用。具体目的2：生成和表征缺乏NKG 2D表达的gone靶向小鼠。具体目的3：评估NKG 2D在体内肿瘤监测中的重要性。具体目的4：确定NKG 2D刺激作为癌症免疫疗法的疗效