Role of NKG2D in immune responses to tumors

描述（由申请人提供）：该提案旨在研究NKG2D免疫受体在肿瘤细胞免疫应答中的功能。NKG2D是一种刺激受体，在所有自然杀伤细胞（NK）、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细胞中表达。NKG2D识别几种相关的细胞表面蛋白（配体），包括雷尔和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的强烈攻击，以及CTL对肿瘤特异性抗原的增强反应。大多数正常细胞不表达这些NKG2D配体。相反，大多数肿瘤细胞系上调雷尔和其他NKG2D配体。待验证的假设是NKG2D及其配体代表肿瘤免疫监视系统。也就是说，研究人员提出NKG2D配体在肿瘤细胞发育过程中正常上调，作为一种提醒和激活免疫系统的手段，由此产生的免疫反应可以限制正常动物肿瘤的发育和/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，经转导表达高水平NKG2D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，刺激针对已建立的同类型肿瘤（但未转导）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地结合。特异性目的1：确定与不同适配器分子相关的NKG2D亚型在刺激和共刺激NKG2D+细胞中的作用。特异性目的2：生成和表征缺乏NKG2D表达的去靶小鼠。特异性目的3：评估NKG2D在体内肿瘤监测中的重要性。特异性目的4：确定NKG2D刺激作为癌症免疫治疗的疗效

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