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应答通常不足以产生足够的临床应答。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得到充分确立，但每个不同DC亚群的作用尚未确定，但对于开发靶向有效免疫方法至关重要。在这个建议中，我们将集中我们的努力，了解不同的DC亚群在慢病毒介导的遗传免疫中的作用和T细胞免疫应答是如何引起的机制。我们推测，皮肤给药慢病毒载体将导致皮肤DC（sDC）的特异性转导和幼稚T细胞的直接引发，这可以用于设计更有效的抗肿瘤基因免疫策略。具体目的如下：目的1：研究慢病毒载体免疫中T细胞引发的机制;目的2：操纵抗原加工途径以引发更有效的T细胞应答;目的3：评估慢病毒载体免疫的抗肿瘤效果。为了实现这些目标，将检查来自慢病毒载体免疫的小鼠的DC亚群的离体和体内引发初始T细胞的功能。将在体内确定初始T细胞的直接与交叉致敏的机制。此外，还将研究利用慢病毒载体免疫诱导针对自身肿瘤抗原的T细胞免疫应答的潜力。将研究通过泛素介导的降解途径促进内源性抗原加工和通过Fc受体呈递外源性抗原以增强T细胞对黑素瘤自身肿瘤Ag TRP-2的应答。我们的研究将产生相关的信息DC亚群，激活T细胞在体内，T细胞是如何在体内引发的机制，以及慢病毒免疫的潜力，在引发T细胞对自身肿瘤抗原的反应。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基因免疫方法。

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.