Nano-therapeutics Reprogramming of Immunosuppressive Myeloid Cells Potentiate Radiotherapy for Glioblastoma

项目总结/摘要 放射治疗（RT）是胶质母细胞瘤（GBM）标准治疗的关键组成部分， 成人常见且致命的原发性脑恶性肿瘤。除了对肿瘤本身的直接细胞毒性作用外，RT- 引发的抗肿瘤免疫应答最近被认为是治疗结果的关键因素。 这些反应依赖于骨髓细胞的功能，骨髓细胞是先天免疫系统的重要组成部分。 免疫系统然而，在肿瘤微环境中，大部分髓样区室被编程为 是免疫抑制性的，其损害抗肿瘤免疫应答，从而损害RT的治疗效果。 这项工作的目的是利用和重编程免疫抑制性肿瘤相关的骨髓细胞， 细胞（TAMCs），GBM中最丰富的免疫群体，以放大RT-诱导的抗肿瘤免疫 应答为了实现TAMC的精确和有效的治疗靶向，我们提出了开发一种新的靶向药物。 桥-脂质纳米颗粒（B-LNP）平台，具有主动靶向体内GBM诱导的TAMC的能力。我们 初步数据表明，B-LNP通过“桥接”效应将TAMC与GBM连接在一起，并同时阻断 GBM用来逃避免疫监视的抗吞噬效应物。该平台还使TAMC- 靶向递送干扰素基因（STING）刺激剂激动剂，STING是桥接先天和 适应性抗肿瘤免疫，导致肿瘤显示促炎表型， 刺激肿瘤的效应T细胞浸润。在临床前动物模型中，我们的TAMC靶向重编程 促进脑肿瘤消退，并增加RT的抗肿瘤活性。 该建议的中心假设是，同时激活TAMC的纳米颗粒疗法 吞噬活性和干扰素途径信号传导将增强RT刺激的抗肿瘤免疫， GBM。我们将专注于我们的纳米颗粒可以利用的TAMC的两种不同的抗GBM机制： GBM的吞噬作用（Aim 1）和效应T细胞应答的活化（Aim 2）。最后，我们将确定 TAMC靶向治疗在GBM标准治疗背景下的有效性（目标3）。的 临床转化的可行性将使用临床前动物模型进行彻底评估，包括独特的 GBM的人源化动物模型和临床GBM样品，其将测试人源化GBM的有效性。 治疗方法的版本。总的来说，我们的研究提供了一种新的方法来重塑免疫抑制因子。 肿瘤微环境负责治疗耐药性，并促进目前的标准护理疗法， GBM。

PROJECT SUMMARY/ABSTRACT Radiation therapy (RT) is a key component of standard of care treatments for glioblastoma (GBM), the most common and deadly primary brain malignancy in adults. Beyond the direct cytotoxic effect on tumor itself, RT- elicited anti-tumor immune responses have recently been appreciated as a key factor to the treatment outcomes. These responses are dependent on the functionality of myeloid cells, an essential component of the innate immune system. However, within tumor microenvironment, much of the myeloid compartment is programed to be immunosuppressive, which impairs the anti-tumor immune responses and thereby therapeutic effects of RT. The objective of this proposed work is to harness and reprogram immunosuppressive tumor-associated myeloid cells (TAMCs), the most abundant immune population in GBM, to amplify the RT-elicited anti-tumor immune responses. To enable a precise and efficient therapeutic targeting of TAMC, we propose the development of a bridge-lipid nanoparticle (B-LNP) platform with the ability to actively target the GBM-induced TAMC in-vivo. Our preliminary data suggest that B-LNP tethers TAMC to GBM through a “bridging” effect and concurrently blocks the anti-phagocytic effectors used by GBM to escape immune surveillance. This platform also enables TAMC- targeted delivery of an agonist for stimulator of interferon genes (STING), a key factor in bridging innate and adaptive anti-tumor immunity, resulting in the tumor displaying a pro-inflammatory phenotype that robustly stimulates effector T cell infiltration of tumor. In preclinical animal models, our TAMC-targeted reprogramming promotes brain tumor regression, and increases the anti-tumor activity of RT. The central hypothesis of this proposal is that nanoparticle therapies that simultaneously activate TAMC phagocytic activity and interferon pathway signaling will amplify the RT-stimulated anti-tumor immunity against GBM. We will focus on two different anti-GBM mechanisms of TAMC that our nanoparticle could harness: phagocytosis of GBM (Aim 1) and activation of effector T cell responses (Aim 2). Lastly, we will determine the effectiveness of TAMC-targeted therapy in the context of standard of care treatments for GBM (Aim 3). The feasibility for clinical translation will be thoroughly evaluated using preclinical animal models, including a unique humanized animal model of GBM, and clinical GBM samples, which will test the effectiveness of a humanized version of the therapeutics. Overall, our study provides a novel approach to reshape the immunosuppressive tumor microenvironment responsible for therapy resistance, and promote current standard of care therapies for GBM.