Enhancing Tumor Antigen Presentation with Complement Targeted Nanoparticles

项目摘要/摘要 活化的抗原提呈细胞(APC)吞噬肿瘤抗原并将其展示给T细胞，启动免疫 对癌症的反应。然而，在癌症患者中，APC通常受到免疫抑制，导致 实体恶性肿瘤的T细胞抑制、肿瘤生长促进和免疫治疗失败。目前， 没有临床治疗方案能够将APC激活为免疫刺激表型，而 同时递送肿瘤抗原以驱动抗原递呈和抗肿瘤免疫。没有新的 加强抗原呈递的方法，癌症免疫治疗可能会继续局限于小范围 患者百分比。在向前迈出的重要一步中，我们的实验室已经开发出一种脂质体递送系统(C3- 脂质体)可以靶向所有三种APC：树突状细胞、巨噬细胞和B细胞(Francian， 2017年)。此外，初步结果表明，C3脂质体运送肿瘤抗原和激活 在小鼠癌症模型中，化合物转化为APC，导致T细胞激活和肿瘤消除。这个 已确定使用C3脂质体改善肿瘤抗原呈递的以下策略。 目的1：评价C3脂质体运送抗原和TLR激动剂联合应用后的免疫应答。 Toll样受体(TLR)激动剂，导致抗原提呈细胞的激活，将被包裹在 C3-脂质体与MHCI和MHCII结合卵清蛋白(OVA)多肽的最佳确定 用来激发免疫反应的配方。 目的2：利用MUC1转基因小鼠模型检测C3脂质体的预防效果。在癌症中 MUC1在超过75%的实体恶性肿瘤中过表达，如乳腺、结直肠、胃、 胰腺癌、膀胱癌和其他癌症，使MUC1成为理想的肿瘤抗原。这一目标的目标是 用转基因小鼠和肿瘤确定C3-脂质体MUC1多肽的预防效果 表达人类MUC1的基因。 目的3：确定C3-脂质体包裹多种肿瘤抗原是否提高了对 检查点免疫疗法。来自B16-F10黑色素瘤细胞系的多种抗原将被递送 使用C3脂质体和检查点阻断免疫疗法来确定治疗A组的疗效 黑色素瘤小鼠癌症模型。 拟议的目标将评估C3脂质体在增强抗原提呈和 产生一种对抗癌症的免疫反应。同时，这项研究还将建设 生物医学研究，大力加强本科生和研究生生物医学研究教育 亚利桑那大学的学生。最终，C3脂质体可以改善肿瘤抗原的传递，当用于 与目前的免疫疗法相结合，提高对治疗有反应的患者百分比。

PROJECT SUMMARY/ABSTRACT Activated Antigen Presenting Cells (APCs) engulf and display tumor antigen to T cells, initiating the immune response against cancer. However, in cancer patients, APCs are often immune suppressed, resulting in inhibition of T cells, promotion of tumor growth and failure of immunotherapy in solid malignancies. At present, there is no clinical treatment option capable of activating APCs to an immune stimulatory phenotype while simultaneously delivering tumor antigen to drive antigen presentation and antitumor immunity. Without new approaches to enhance antigen presentation, cancer immunotherapy will likely continue to be limited to a small percentage of patients. In a significant step forward, our lab has developed a liposome delivery system (C3- liposomes) that can target all three APCs: dendritic cells, macrophages and B cells (Francian, 2017). Furthermore, preliminary results indicate that C3-liposomes deliver tumor antigen and activating compounds to APCs, leading to T cell activation and elimination of tumors in a murine cancer model. The following strategies have been identified for improving tumor antigen presentation using C3-liposomes. Aim 1: Evaluate immune response to C3-liposome delivery of antigen and TLR agonist combinations. Toll-like receptor (TLR) agonists, which lead to activation of Antigen Presenting Cells, will be encapsulated in C3-liposomes along with MHCI and MHCII binding ovalbumin (OVA) peptides to determine the optimal formulation for eliciting an immune response. Aim 2: Examine C3-liposome prophylactic efficacy using a MUC1 transgenic mouse model. In cancer patients, MUC1 is overexpressed in more than 75% of solid malignancies such as breast, colorectal, stomach, pancreatic, bladder and other cancers, making MUC1 an ideal tumor antigen. The goal of this aim is to determine the prophylactic benefit of C3-liposome MUC1 peptide delivery using transgenic mice and tumors that express human MUC1. Aim 3: Determine if C3-liposome encapsulation of multiple tumor antigens improves responsiveness to checkpoint immunotherapy. Multiple antigens from the B16-F10 melanoma tumor cell line will be delivered with C3-liposomes and tested with checkpoint blockade immunotherapy to determine efficacy in treating a melanoma mouse model of cancer. The proposed aims will evaluate the effectiveness of C3-liposomes for enhancing antigen presentation and creating an immune response against cancer. At the same time, this study will also build capacity for biomedical research and significantly enhance biomedical research education for undergraduate and graduate students at UAA. Ultimately, C3-liposomes could improve tumor antigen delivery and when used in combination with current immunotherapy, increase the percentage of patients who respond to treatment.