Anti-tumorigenic Activity of Adenovirus E1A

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。为了优化这种治疗形式，我们必须了解E1A抗肿瘤作用的分子基础。我们发现：E1A引发强烈的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，而不是不能与细胞转录共接头分子p300或CBP（简称E1A- ap300）相互作用的突变形式的E1A，增加了肿瘤细胞表面NKG2D配体的表达。因此，表达E1A的肿瘤细胞在体内以依赖于nkg2d的方式被NK细胞清除。NKG2D配体的上调有助于E1 A介导的免疫介导的致瘤性降低。目前E1A在治疗人类恶性肿瘤中的应用并没有利用E1A免疫介导的抗肿瘤活性。本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的中，我们将探索E1A与p300或高度相关的转录共接头蛋白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+， E1 a特异性T细胞反应，或者是否涉及E1A的其他促免疫原性活性。在第三个目标中，我们将确定E1A是否可以作为分子佐剂引发抗原特异性抗肿瘤免疫反应。目的1：确定E1A（而不是E1A- ap300）增加NKG2D配体表达能力的分子机制。目的2：确定表达E1A的肿瘤细胞引发的强大的E1 a特异性CD+8 T细胞反应的分子基础。目的3：确定E1A的促免疫原性活性是否可以被利用来引发强烈的肿瘤抗原特异性免疫反应。

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.