Enhancing Immunotherapy through Toll Like Receptors

描述(申请人提供)：癌症免疫治疗的目标是诱导抗肿瘤免疫反应。注射肿瘤抗原进行免疫治疗会导致T细胞反应较弱，由于缺乏良好的佐剂而无效。病原体相关分子模式(PAMPs)作为候选疫苗佐剂近来受到重视。PAMP是一种分子签名，它定义了微生物的类别，并诱导了强大的免疫反应。这项研究的长期目标是了解PAMPs在其受体Toll样受体(TLRs)上激活的分子机制。TLRs的调节和PAMPs的修饰将极大地增强肿瘤疫苗的佐剂作用，从而改善肿瘤的免疫治疗。在这一授权期内，我们将确定Toll样受体亚家族(3、7、8和9)中PAMP识别和受体运输的控制机制。这些跨膜Toll样受体的共同特点是它们不在细胞表面表达，它们识别dsRNA(TLR3)、ssRNA(TLR7和TLR8)和含有DNA的CpG(TLR9)等核酸。我们假设识别Toll样受体的核酸具有共同的定位、运输和PAMP识别机制，这些机制由细胞质和胞外区域的离散序列控制。我们将在两个具体目标上检验这一假设。首先，我们将确定识别Toll样受体的核酸在PAMPs反应中的定位和运输的分子机制。其次，我们将确定相应PAMP配体在TLRs上的特定结合区域。这些信息将填补Toll样受体-PAMP生物学知识的空白：配体识别的分子基础，以及细胞靶向在控制信号传递中的作用。这些信息将允许开发新的治疗策略来调节免疫反应，以改进癌症疫苗佐剂。这笔职业过渡拨款将使我能够开发一个研究计划，专注于利用TLR-PAMP生物学治疗人类癌症的新方法。

DESCRIPTION (provided by applicant): The goal of cancer immunotherapy is to elicit anti-tumor immune responses. Injecting tumor antigens for immunotherapy results in T cell responses that are weak and ineffective due to a lack of good adjuvants. Recent emphasis has been on pathogen associated molecular patterns (PAMPs) as candidate vaccine adjuvants. PAMPs are molecular signatures that define classes of microorganisms and induce potent immune responses. The long-term goal of the proposed studies is to understand the molecular mechanisms of activation of PAMPs on their receptors, Toll like receptors (TLRs). Modulation of TLRs and modification of PAMPs will greatly enhance cancer vaccine adjuvanticity thereby improving immunotherapy of cancer. In this grant period we will determine control mechanisms for PAMP recognition and receptor trafficking in a subfamily of Toll like receptors (3, 7, 8 and 9). These transmembrane Toll like receptors share the properties that they are not expressed at the cell surface and that they recognize nucleic acids such as dsRNA (TLR3), ssRNA (TLR7 and TLR8) and CpG containing DNA (TLR9). We hypothesize that nucleic acid recognizing Toll like receptors share localization, trafficking and PAMP recognition mechanisms that are controlled by discrete sequences in the cytoplasmic and ectodomains. We will test the hypothesis in two specific aims. First, we will determine the molecular mechanisms of localization and trafficking of nucleic acid recognizing Toll like receptors in response to PAMPs. Second, we will determine the specific binding regions on TLRs for the corresponding PAMP ligand. This information will fill gaps in the knowledge of Toll like receptor-PAMP biology: the molecular basis of ligand recognition, and the role of cellular targeting in controlling signaling. This information will allow the development of novel therapeutic strategies to modulate the immune responses to improve cancer vaccine adjuvants. This career transition grant will allow me to develop a research program focused on new ways to exploit TLR-PAMP biology for the treatment of human cancer.