Role of NKG2D in immune responses to turmors

NKG2D 在肿瘤免疫反应中的作用

• 批准号: 8259460
• 负责人: DAVID H RAULET
• 金额: $ 25.88万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259460
• 关键词: Accounting; Address; Adenocarcinoma; Adoptive Transfer; Affect; Animals; Antitumor Response; CD8 receptor; CD8B1 gene; Cancer Model; Carcinogens; Cell Maintenance; Cells; Cytolysis; DNA Damage; Data; Development; Diagnostic Neoplasm Staging; Exhibits; Funding; Genetic; Histopathology; Immune; Immune response; Immune system; Immunologic Surveillance; In Vitro; Incidence; Infiltration; Knock-out; Knockout Mice; Ligands; MHC Class I Genes; Malignant Neoplasms; Mediating; Memory; Methods; Modeling; Mus; Mutation; Natural Killer Cells; Normal Cell; Oncogenes; Oncogenic; Pathway interactions; Pattern; Premalignant Cell; Primary Neoplasm; Prostate; Prostate Adenocarcinoma; Proteins; Reporting; Research; Role; Series; Signal Transduction; Staging; Stress; Surface; System; T cell response; T-Lymphocyte; Testing; Therapeutic Agents; Time; Transgenic Mice; Transgenic Organisms; Tumor Cell Line; Tumor Suppression; Tumor stage; Uncertainty; Up-Regulation; Viral Tumor Antigens; cancer cell; cell type; cohort; design; fibrosarcoma; in vivo; killings; mouse model; neoplastic cell; receptor; research study; response; senescence; tumor; tumor initiation; tumorigenesis

The NKG2D stimulatory receptor, expressed by NK cells, CD8+, and other T cells, recognizes self ligands that are poorly expressed by normal cells and upregulated by various tumor cells. Expression of NKG2D ligands by tumor cells sensitizes the cells to lysis by NK cells and in some cases T cells. Our central hypothesis is that NKG2D serves (in part) as a host tumor surveillance apparatus that enables NK cells and T cells to eliminate very early stage tumor cells that upregulate NKG2D ligands as a result of oncogenic stress To address key aspects of this hypothesis, we have generated Nkg2d-/- mice. Studies in the previous funding period demonstrated that Nkg2d-/- mice are impaired in immune surveillance of a highly aggressive, early- arising form of prostate adenocarcinoma in the TRAMP oncogene-transgenic mice, and in surveillance of fibrosarcomas induced by the carcinogene methylcolanthrene. We propose here to investigate several key mechanistic issues of NKG2Ds role in cancer immune-surveillance. Specific Aim 1 will address whether NK cells and/or T cells mediate NKG2D-mediated surveillance in cancer models in vivo. We will use genetic studies combining NKG2D knockout mice with mice deficient for NK cells and/or T cells to determine whether NKG2D surveillance is primarily mediated by NK cells, T cells, or both. Specific Aim 2 will address the role of NKG2D specifically on CD8 T cells in specific antitumor responses in vivo. Because of controversy surrounding the role of NKG2D in enhancing CD8 T cell responses to tumors, we will use defined TCR transgenic T cells from NKG2D knockout or wildtype mice in an adoptive transfer/tumor challenge model, in order to address whether NKG2D expressed by CD8 T cells enhances initial proliferative and functional responses, formation of memory cells, maintenance of functionality in the memory stage and capacity to reject tumors. Specific Aim 3 will determine whether NKG2D-dependent surveillance of TRAMP tumors occurs at the stage of tumor initiation. Our central hypothesis is that NKG2D surveillance is a consequence of NKG2D ligand upregulation resulting from pathways that serve as the earliest barriers to tumorigenesis. It is critical to determine whether surveillance occurs at such an early stage, or later. To address the proposal that NKG2D-dependent surveillance acts at the earliest stages of tumor initiation, or later, we will investigate tumor formation in timed cohorts of wildtype or NKG2D knockout mice, using NKG2D ligand expression patterns, histopathology analysis, and analysis of immune infiltrates as methods to pinpoint the stage at which surveillance occurs and its relation to ligand expression and immune cell infiltration. This comprehensive series of experiments will definitively test the role of NKG2D in NK cells and T cells, their interactions, the influence of NKG2D on CD8 T cell responses, and whether NKG2D acts on early or precancerous cells as opposed to more advanced tumors. There is no doubt that the conclusions of these studies will provide fundamental understanding of NKG2Ds role. This research addresses how the immune response attacks cancer cells. We are testing the hypothesis that a specific receptor protein called NKG2D on the surface of immune cells enables these cells to attack and kill cancer cells. The preliminary results show that animals that lack the protein due to a mutation have a higher incidence of cancer. Yet some cancer cells escape recognition by this recognition system. The results of our results will help to guide the design of therapeutic agents that help our immune systems attack cancer.

由NK细胞、CD 8+和其他T细胞表达的NKG 2D刺激性受体识别自身配体， 在正常细胞中表达不足，在各种肿瘤细胞中表达上调。NKG 2D配体的表达 肿瘤细胞使细胞对NK细胞和在某些情况下T细胞的裂解敏感。我们的核心假设是， NKG 2D（部分）作为宿主肿瘤监视装置，使NK细胞和T细胞能够 消除因致癌应激而上调NKG 2D配体的极早期肿瘤细胞 为了解决这一假设的关键方面，我们产生了Nkg 2d-/-小鼠。以往资助的研究 Nkg 2d-/-小鼠在对高度侵袭性的、早期的 在TRAMP癌基因转基因小鼠中前列腺腺癌的发生形式，以及在监测 由致癌基因methylcolanthrene诱发的纤维肉瘤。我们在这里建议调查几个关键 NKG 2D在癌症免疫监视中作用的机制问题。具体目标1将涉及北朝鲜是否 细胞和/或T细胞在体内癌症模型中介导NKG 2D介导的监视。我们将使用基因 研究将NKG 2D敲除小鼠与NK细胞和/或T细胞缺陷小鼠相结合，以确定 NKG 2D监测主要由NK细胞、T细胞或两者介导。具体目标2将讨论 在体内特异性抗肿瘤应答中，NKG 2D特异性作用于CD 8 T细胞。因为争议 围绕NKG 2D在增强CD 8 T细胞对肿瘤应答中的作用，我们将使用定义的TCR 过继转移/肿瘤激发模型中来自NKG 2D敲除或野生型小鼠的转基因T细胞， 为了解决由CD 8 T细胞表达的NKG 2D是否增强初始增殖和功能 反应，记忆细胞的形成，记忆阶段功能的维持和拒绝能力 肿瘤的具体目标3将确定TRAMP肿瘤的NKG 2D依赖性监测是否发生 在肿瘤发生的阶段。我们的中心假设是NKG 2D监测是以下因素的结果： NKG 2D配体上调由作为肿瘤发生最早屏障的途径引起。是 关键是要确定监视是否发生在这样的早期阶段，或以后。为了解决以下建议， NKG 2D依赖性监测在肿瘤起始的最早阶段起作用，或者稍后，我们将研究肿瘤 使用NKG 2D配体表达模式，在野生型或NKG 2D敲除小鼠的定时队列中形成， 组织病理学分析和免疫浸润分析作为确定 监视发生及其与配体表达和免疫细胞浸润的关系。这一综合系列 的实验将明确测试NKG 2D在NK细胞和T细胞中的作用，它们的相互作用， NKG 2D对CD 8 T细胞应答的影响，以及NKG 2D是否作用于早期或癌前细胞， 更严重的肿瘤毫无疑问，这些研究的结论将提供基本的 了解NKG 2D的作用。这项研究解决了免疫反应如何攻击癌细胞。我们正在测试 假设免疫细胞表面的一种称为NKG 2D的特异性受体蛋白 使这些细胞能够攻击并杀死癌细胞。初步结果显示， 由于突变而缺乏这种蛋白质的动物患癌症的几率更高。然而 一些癌细胞逃脱了该识别系统的识别。我们的结果 将有助于指导治疗剂的设计，帮助我们的免疫系统攻击 癌