Mechanism of Eliciting Antitumor Cell Immunity Via Lentivector Immunization

描述（由申请人提供）：免疫疗法代表了最有前途的癌症治疗方式之一。然而，当前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。有效免疫方法的开发最终需要基于对免疫细胞如何激活的详细了解的合理设计。 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，但对于开发有针对性的有效免疫方法至关重要。在本提案中，我们将集中精力了解不同 DC 亚群在慢载体介导的基因免疫中的作用以及如何引发 T 细胞免疫反应的机制。我们假设慢载体的皮肤给药将导致皮肤 DC (sDC) 的特异性转导和初始 T 细胞的直接启动，这可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：研究慢载体免疫中T细胞启动的机制；目标 2：操纵抗原加工途径以引发更有效的 T 细胞反应；目标3：评估慢载体免疫的抗肿瘤效果。为了实现这些目标，将检查慢载体免疫小鼠的 DC 亚群在离体和体内启动幼稚 T 细胞的功能。初始 T 细胞的直接与交叉引发机制将在体内确定。此外，还将研究利用慢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抗原加工和通过Fc受体呈递外源抗原，以增强针对黑色素瘤自身肿瘤Ag TRP-2的T细胞反应。我们的研究将产生与体内激活 T 细胞的 DC 亚群相关的信息、T 细胞在体内启动的机制，以及慢病毒载体免疫在引发针对自身肿瘤 Ag 的 T 细胞反应中的潜力。从这些研究中获得的知识将有助于设计更有效、更安全的抗肿瘤免疫治疗基因免疫方法。

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.