Mechanism of Eliciting Antitumor Cell Immunity Via Lentivector Immunization

描述(申请人提供)：免疫疗法是最有前途的癌症治疗方法之一。然而，目前的免疫方法诱导的免疫反应一般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对免疫细胞如何激活的详细知识进行合理的设计。DC作为整个群体的抗原提呈功能已经得到很好的确立，但每个不同的DC亚群的作用尚未确定，但对于开发有针对性的有效免疫方法至关重要。在这项建议中，我们将集中精力了解不同的DC亚群在慢病毒载体介导的遗传免疫中的作用以及T细胞免疫应答的机制。我们假设，慢载体的皮肤给药将导致皮肤树突状细胞(SDCs)的特异性转导和初始T细胞的直接激发，这将被用于设计更有效的抗肿瘤基因免疫策略。其具体目的如下：目的1：探讨慢载体免疫中T细胞启动的机制；目的2：操纵抗原处理途径以诱导更有效的T细胞应答；目的3：评价慢载体免疫的抗肿瘤效果。为了达到这些目的，将检测慢载体免疫小鼠的DC亚群在体外和体内对初始T细胞的激活功能。初始T细胞的直接激发和交叉激发的机制将在体内确定。此外，还将探讨利用慢载体免疫来诱导针对自身肿瘤抗原的T细胞免疫反应的可能性。通过泛素介导的降解途径促进内源性抗原加工和Fc受体递呈外源性抗原，以增强T细胞对黑色素瘤自身瘤抗原Trp-2的应答。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细胞在体内如何被启动的机制，以及慢载体免疫在诱导T细胞对自身肿瘤抗原的反应中的潜力。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.