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，CD8+和其他T细胞表达的NKG2D刺激受体识别自我配体 正常细胞表达不佳，并被各种肿瘤细胞上调。 NKG2D配体的表达 肿瘤细胞使细胞通过NK细胞和在某些情况下T细胞溶解细胞。我们的中心假设是 NKG2D（部分）用作宿主肿瘤监测设备，使NK细胞和T细胞达到 消除非常早期的肿瘤细胞，这些细胞上调了由于致癌应激而导致NKG2D配体 为了解决该假设的关键方面，我们生成了NKG2D - / - 小鼠。以前的资金研究 时期表明NKG2D - / - 小鼠在免疫监测中受到了高度侵略性，早期 - 在流浪性癌基因转基因小鼠中引起的前列腺腺癌的形式，并监视 癌细胞甲基丙烯蛋白诱导的纤维肉瘤。我们在这里建议调查几个关键 NKG2DS在癌症免疫传球中的作用的机理问题。具体目标1将解决NK是否 细胞和/或T细胞介导体内癌症模型中NKG2D介导的监测。我们将使用遗传 研究NKG2D敲除小鼠与缺乏NK细胞和/或T细胞的小鼠的研究，以确定是否是否 NKG2D监测主要由NK细胞，T细胞或两者兼而有之。特定目标2将解决该角色 在体内特定抗肿瘤反应中，专门针对CD8 T细胞的NKG2D。由于争议 围绕NKG2D在增强CD8 T细胞对肿瘤的反应中的作用，我们将使用定义的TCR 在收养转移/肿瘤挑战模型中，来自NKG2D敲除或野生型小鼠的转基因T细胞在 为了解决CD8 T细胞表达的NKG2D是否增强了初始增殖和功能 响应，记忆单元的形成，在内存阶段维持功能的维护以及拒绝的能力 肿瘤。具体目标3将确定是否发生NKG2D依赖性监测 在肿瘤开始的阶段。我们的核心假设是NKG2D监视是 NKG2D配体上调是由最早的肿瘤发生障碍而产生的。这是 至关重要的是确定监视是在这样的早期阶段还是更晚的。解决以下提议 NKG2D依赖性监测行为在肿瘤起始的最早阶段，或者以后，我们将研究肿瘤 使用NKG2D配体表达模式的野生型或NKG2D敲除小鼠的定时组中形成 组织病理学分析和免疫浸润物作为查明阶段的方法 进行监测及其与配体表达和免疫细胞浸润的关系。这个全面的系列 实验的实验将确定测试NKG2D在NK细胞和T细胞中的作用，它们的相互作用，其影响 CD8 T细胞反应上的NKG2D，NKG2D是对早期还是癌细胞的作用，而不是 更高级的肿瘤。毫无疑问，这些研究的结论将提供基本 了解NKG2DS角色。这项研究解决了免疫反应如何攻击癌细胞。我们正在测试 假设免疫细胞表面上称为NKG2D的特定受体蛋白 使这些细胞能够攻击并杀死癌细胞。初步结果表明 由于突变而缺乏蛋白质的动物的癌症发生率更高。然而 一些癌细胞通过此识别系统逃脱了识别。我们结果的结果 将有助于指导治疗剂的设计，以帮助我们的免疫系统攻击 癌症。