Scavenger Receptor-A and Immune Regulation

描述（由申请人提供）：癌症疫苗代表了一种有前途的免疫方法，但迄今为止在临床上仅取得了有限的成功。成功的癌症免疫治疗的主要挑战之一是存在内在免疫抑制机制，其可以抑制针对肿瘤相关自身抗原的有效免疫的诱导。这些免疫抑制调节剂的知识可以在治疗上用于提高疫苗治疗癌症的功效。在清道夫受体-A（SR-A）（一种主要表达于抗原呈递细胞（APC）上的模式识别受体）的研究中，我们的实验室意外地发现，缺乏SR-A显著增强了疫苗产生的针对免疫原性差的肿瘤的免疫力。这些发现首次证明SR-A能够减弱内源性和外源性“危险”分子提供的免疫佐剂效应。此外，来自SR-A缺陷小鼠的抗原呈递细胞，例如树突状细胞（DC），对炎性刺激（例如，TLR激动剂），并且与来自野生型对应物的那些相比显示出更有效的免疫刺激能力。基于这些观察，我们假设清道夫受体-A是一个以前未被认识的抗原特异性免疫抑制剂。所提出的研究的总体目标是了解在SR-A缺陷小鼠中观察到的增强的抗肿瘤应答的免疫学和生物化学机制，并评估沉默SR-A作为增强疫苗效力的方法的可行性。我们计划通过追求以下具体目标来验证中心假设并实现本提案的目标：1）确定SR-A在APC免疫功能和抗原特异性适应性免疫反应中的调节作用; 2）确定SR-A调节Toll样受体介导的分子机制-在树突状细胞中介导的信号传导;和3）使用临床相关模型测定SR-A沉默的树突细胞促进抗原特异性CTL应答和长期抗肿瘤免疫的能力。对SR-A对宿主免疫或耐受的整体贡献的剖析，以及解开由该受体调节的TLR介导的炎症途径的分子细节，将提供关于SR-A在免疫稳态功能中的作用的重要信息。此外，成功测试SR-A沉默的树突细胞作为疫苗以打破针对肿瘤相关自身抗原的耐受性将提供靶向抑制性先天受体的新型免疫抑制方法。

DESCRIPTION (provided by applicant): Cancer vaccines represent a promising immunotherapeutic approach, but thus far have achieved only limited success in the clinic. One of the major challenges to successful cancer immunotherapy is the presence of intrinsic immune inhibitory mechanisms that can dampen induction of effective immunity against tumor-associated self antigens. Knowledge of these immunosuppressive regulators could be exploited therapeutically to improve vaccine efficacy for the treatment of cancer. During studies of scavenger receptor-A (SR-A), a pattern recognition receptor primarily expressed on antigen presenting cells (APCs), our laboratory made an unexpected discovery that lack of SR-A significantly enhanced vaccine-generated immunity against poorly immunogenic tumors. The findings, for the first time, demonstrate that SR-A is able to attenuate immune-adjuvant effects provided by both endogenous and exogenous 'danger' molecules. Furthermore, antigen-presenting cells from SR-A deficient mice, such as dendritic cells (DCs), are more responsive to inflammatory stimuli (e.g., TLR agonists) and display a more potent immunostimulatory capability compared to those from wild-type counterparts. Based on these observations we hypothesize that scavenger receptor-A is a previously unrecognized repressor of antigen-specific immunity. The overall objectives of the proposed research are to understand the immunological and biochemical mechanisms underling the enhanced antitumor response observed in SR- A deficient mice, and to evaluate the feasibility of silencing SR-A as an approach to enhance vaccine efficacy. We plan to test the central hypothesis and accomplish the objective of this proposal by pursuing the following specific aims: 1) Determine the regulatory roles of SR-A in immunological .functions of APCs and antigen-specific adaptive immune responses; 2) Determine the molecular mechanisms by which SR-A modulates Toll-like receptor-mediated signaling in dendritic cells; and 3) Determine the ability of SR-A-silenced dendritic cells to promote an antigen-specific CTL response and long-term antitumor immunity using clinically relevant models. Dissection of the global contribution of SR-A to host immunity or tolerance, and unraveling the molecular details of TLR-mediated inflammatory pathways modulated by this receptor will provide essential information on the role of SR-A in immune homeostatic functions. Further, successful testing of SR-A-silenced dendritic cells as a vaccine to break tolerance against tumor- associated self-antigens will provide a novel immunotherapeutic approach targeting the inhibitory innate receptor.