Mechanism of Eliciting Antitumor Cell Immunity Via Lentivector Immunization

描述（由申请人提供）：免疫疗法是最有前途的癌症治疗方式之一。然而，目前的免疫方法诱导的免疫反应通常不足以产生足够的临床反应。开发有效的免疫方法最终需要基于免疫细胞如何被激活的详细知识的合理设计。DC作为整个群体的抗原呈递功能已经得到了很好的确定，但每个不同DC亚群的作用尚未确定，但对于开发靶向有效的免疫方法至关重要。在本提案中，我们将重点了解不同DC亚群在慢载体介导的遗传免疫中的作用以及如何引发T细胞免疫反应的机制。我们假设皮肤给予慢载体将导致皮肤dc （sdc）的特异性转导和直接启动幼稚T细胞，这可以用于设计更有效的抗肿瘤遗传免疫策略。具体目的如下：目的1：探讨T细胞启动慢载体免疫的机制；目的2：操纵抗原加工途径以引发更有效的T细胞反应；目的3：评价慢载体免疫的抗肿瘤效果。为了实现这些目标，慢载体免疫小鼠的DC亚群将被检测其在体内和体外启动初始T细胞的功能。将在体内确定初始T细胞直接与交叉启动的机制。此外，利用慢载体免疫诱导T细胞免疫反应对抗自身肿瘤抗原的潜力也将被研究。将研究通过泛素介导的降解途径促进内源性抗原加工和Fc受体的外源性抗原呈递，以增强T细胞对黑色素瘤自身肿瘤Ag TRP-2的反应。我们的研究将提供与体内激活T细胞的DC亚群相关的信息，T细胞在体内启动的机制，以及慢载体免疫在诱导T细胞对自身肿瘤Ag反应中的潜力。从这些研究中获得的知识将有助于设计更有效和更安全的抗肿瘤免疫治疗的遗传免疫方法。

DESCRIPTION (provided by applicant): Immunotherapy represents one of the most promising therapeutic modalities for cancer. However, the immune responses induced by current immunization approaches are generally insufficient to generate adequate clinical responses. Development of effective immunization approaches ultimately require rational designs based on detailed knowledge of how immune cells are activated. The antigen presenting function of DCs as whole population is well established, but the role of each distinct DC subset has not been defined but is critical for developing targeted effective immunization approaches. In this proposal we will focus our effort on understanding the roles of the different DC subsets in lentivector mediated genetic immunization and the mechanism of how T cell immune response is elicited. We hypothesize that cutaneous administration of lentivector will result in specific transduction of skin DCs (sDCs) and direct priming of naive T cells, which can exploited for designing more effective antitumor genetic immunization strategies. The specific Aims are as follows: Aim 1: To investigate the mechanism of T cell priming in lentivector immunization; Aim 2: To manipulate antigen processing pathways to elicit more effective T cell responses; and Aim 3: To evaluate the antitumor effectiveness of lentivector immunization. To accomplish these aims, DC subsets from lentivector immunized mice will be examined for their function of priming naive T cells ex vivo and in vivo. The mechanism of direct vs cross priming of naive T cells will be determined in vivo. In addition, the potential of utilizing lentivector immunization in inducing T cell immune responses against self tumor antigen will also be investigated. Promotion of endogenous antigen processing by ubiquitin mediated degradation pathway and exogenous antigen presentation by Fc receptor will be investigated to enhance T cell responses against melanoma self tumor Ag TRP-2. Our study will yield information pertinent to DC subsets that activate T cells in vivo, the mechanism how T cell are primed in vivo, and the potential of lentivector immunization in eliciting T cell responses against self tumor Ag. The knowledge gained from these studies will assist the design of more effective and safer genetic immunization approaches for antitumor immunotherapy.