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

项目摘要/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，是最常见的 成人常见且致命的原发脑部恶性肿瘤。除了对肿瘤本身的直接细胞毒作用外，RT- 最近，抗肿瘤免疫反应被认为是影响治疗结果的一个关键因素。 这些反应依赖于髓系细胞的功能，髓系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，髓系室的大部分被编程为 免疫抑制，这会损害抗肿瘤免疫反应，从而影响RT的治疗效果。 这项拟议工作的目标是利用和重新编程免疫抑制的肿瘤相关髓系。 肾小管上皮细胞(TAMCs)是GBM中最丰富的免疫群体，用于放大RT诱导的抗肿瘤免疫 回应。为了能够精确和有效地治疗TAMC，我们建议开发一种 桥联脂质纳米粒(B-LNP)平台能够在体内主动靶向GBM诱导的TAMC。我们的 初步数据显示，B-LNP通过“桥接”效应将TAMC与GBM连接起来，并同时阻断 GBM用来逃避免疫监视的抗吞噬效应器。该平台还支持TAMC- 靶向递送干扰素基因刺激物激动剂(STING)，这是连接先天性和 适应性抗肿瘤免疫，导致肿瘤表现出强烈的促炎表型 刺激效应T细胞对肿瘤的侵袭。在临床前动物模型中，我们的TAMC靶向重编程 促进脑瘤消退，增强RT的抗肿瘤活性。 这一提议的中心假设是，同时激活TAMC的纳米颗粒疗法 巨噬细胞吞噬活性和干扰素信号通路将增强RT刺激的抗肿瘤免疫 GBM。我们将重点研究我们的纳米颗粒可以利用的两种不同的TAMC抗GBM机制： 吞噬GBM(目标1)和激活效应性T细胞反应(目标2)。最后，我们将确定 TAMC靶向治疗在GBM护理标准治疗背景下的有效性(目标3)。这个 临床移植的可行性将使用临床前动物模型进行彻底评估，包括一个独特的 人性化的基底膜动物模型，以及临床的基底膜标本，这将检验人性化的效果 治疗学的版本。总体而言，我们的研究提供了一种新的方法来重塑免疫抑制 肿瘤微环境对治疗的抵抗力，并促进当前标准的护理治疗 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.