Anti-tumorigenic Activity of Adenovirus E1A

腺病毒E1A的抗肿瘤活性

• 批准号: 7901489
• 负责人: John Michael Routes
• 金额: $ 28.79万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-14 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901489
• 关键词: Abbreviations; Adenoviruses; Adjuvant; Antigen-Presenting Cells; Antigens; Binding; Binding Proteins; CD8B1 gene; CREB-binding protein; Cells; Clinical Treatment; Clinical Trials; Complement 3d Receptors; Cytolysis; Cytotoxic T-Lymphocytes; Dendritic Cells; EP300 gene; Heat shock proteins; Human; Human Papillomavirus; Human papillomavirus 16; Immune; Immune response; Injection of therapeutic agent; Ligands; Malignant Neoplasms; Mediating; Molecular; Monoclonal Antibodies; Mus; Natural Killer Cells; Phase; Serotyping; Surface; T cell response; T-Lymphocyte; Transgenic Mice; Tumor Antigens; Tumorigenicity; Umbilical Cord Blood; Up-Regulation; Viral Oncogene; base; immunogenic; in vivo; mutant; neoplastic cell; response; tumor; tumorigenic

DESCRIPTION (provided by applicant): Adenovirus (Ad) E1A is presently in phase l/ll clinical trials for the treatment of human malignancy. In order to optimize this form of therapy, we must understand the molecular basis for the anti-tumorigenic effect of E1A. We established that: the capacity of E1A to elicit a vigorous NK cell and T cell anti-tumor immune response is an important component of the anti-tumorigenic activity of E1A. The expression of E1A, but not mutant forms of E1A unable to interact with the cellular transcriptional co-adaptor molecules p300 or CBP (abbreviated E1A-Ap300), increases the expression of NKG2D ligands on the surface of tumor cells. Consequently, tumor cells that express E1A are eliminated by NK cells in vivo in a NKG2D-dependent manner. The upregulation of NKG2D ligands contributes to the immune-mediated decrease in tumorigenicity mediated by E1 A. The present use of E1A in the treatment of human malignancy does not exploit the immune-mediated, anti-tumorigenic activity of E1A. Studies in this proposal will define the molecular basis for the immune-mediated, anti-tumorigenic activity of E1A. In the first aim of the proposal we will explore the molecular mechanism whereby the interaction of E1A with p300 or the highly related transcriptional coadaptor protein, CBP, increases the expression of NKG2D ligands on the surface of tumor cells. In the second aim we will determine if the upregulation of NKG2D ligands on tumor cells by E1A is sufficient to induce a CD8+, E1 A-specific T cell response or if other pro-immunogenic activities of E1A are involved. In third aim, we will ascertain if E1A can be used as a molecular adjuvant to elicit antigen-specific anti-tumor immune responses Aim 1: Determine the molecular mechanisms for the ability of E1A, but not E1A-Ap300, to increase the expression of NKG2D ligands. Aim 2: Determine the molecular basis for the robust, E1 A-specific, CD+8 T cell response elicited by tumor cells that express E1A. Aim 3: Determine if the pro-immunogenic activities of E1A can be harnessed to elicit vigorous tumor antigen-specific immune responses.

描述（由申请人提供）：腺病毒（Ad）E1A目前正处于治疗人类恶性肿瘤的I/II期临床试验中。为了优化这种疗法，我们必须了解 E1A 抗肿瘤作用的分子基础。我们确定：E1A 引发旺盛的 NK 细胞和 T 细胞抗肿瘤免疫反应的能力是 E1A 抗肿瘤活性的重要组成部分。 E1A 的表达（但不能与细胞转录辅助接头分子 p300 或 CBP（缩写为 E1A-Ap300）相互作用的 E1A 突变形式）增加肿瘤细胞表面 NKG2D 配体的表达。因此，表达 E1A 的肿瘤细胞在体内被 NK 细胞以 NKG2D 依赖性方式消除。 NKG2D配体的上调有助于免疫介导的E1A介导的致瘤性降低。目前E1A在治疗人类恶性肿瘤中的应用并未利用E1A的免疫介导的抗肿瘤发生活性。该提案中的研究将确定 E1A 免疫介导的抗肿瘤活性的分子基础。在该提案的第一个目标中，我们将探索 E1A 与 p300 或高度相关的转录辅助蛋白 CBP 相互作用增加肿瘤细胞表面 NKG2D 配体表达的分子机制。在第二个目标中，我们将确定 E1A 对肿瘤细胞上 NKG2D 配体的上调是否足以诱导 CD8+、E1A 特异性 T 细胞反应，或者是否涉及 E1A 的其他促免疫活性。第三个目标是，我们将确定 E1A 是否可以用作分子佐剂来引发抗原特异性抗肿瘤免疫反应。 目标 1：确定 E1A（而非 E1A-Ap300）增加 mRNA 表达的分子机制。 NKG2D 配体。目标 2：确定表达 E1A 的肿瘤细胞引发的强效 E1 A 特异性 CD+8 T 细胞反应的分子基础。目标 3：确定是否可以利用 E1A 的促免疫原活性来引发强烈的肿瘤抗原特异性免疫反应。