Fatty Acid Metabolic Regulation of Anti-Tumor Immunity Against Irradiated Glioblastoma

项目总结 胶质母细胞瘤(GBM)是一种破坏性的脑肿瘤疾病，中位总存活率约为15%。 月份。GBM患者的死亡是因为GBM持续获得抵抗机制 抗癌治疗，因此导致不可避免的肿瘤复发。 放射治疗(RT)是提高GBM总存活率的关键手段。然而，GBM总是 复发，这表明RT正在诱发或加剧GBM的耐药机制。识别和 克服与GBM抗性有关的促成因素是辐射方面的主要挑战。 肿瘤学。GBM代谢及其在免疫逃避中的作用作为RT诱导的抵抗机制 单位为GBM。具体地说，我们有初步数据表明，受辐射的GBM细胞重新编程它们的新陈代谢 向脂肪酸的生成迈进。RT后的这种代谢重新编程正在损害先天免疫 RT诱导的识别和系统抗肿瘤免疫。更准确地说，我们有初步证据表明 脂肪酸合成抑制核酸感应依赖型干扰素-I反应，并 促进免疫抑制信号，如程序性死亡1(PD-1)和程序性死亡 配体1(Pd-L1)。因此，肿瘤细胞固有的干扰素-I不会在RT反应中释放。这 最终通过阻止效应T细胞进入基底膜来限制抗肿瘤免疫反应 微环境。我们最近已经证明，癌细胞固有的干扰素-I反应是一个必不可少的步骤 以传递受辐射肿瘤的免疫原性。因此，通过增加能源供应，限制固有的 免疫和日益增强的免疫抑制，RT诱导的脂肪酸合成可能是一种主要的GBM 耐药机制不仅影响GBM的RT反应，而且提供逃避免疫的手段 承认。在这个应用中，我们建议测试新的和创新的假设，即脂肪酸 RT诱导的代谢控制免疫逃逸和GBM存活。成功完成这项工作 该提案将定义脂肪酸合成如何促进GBM免疫逃避，并提供临床前 有证据表明，脂肪酸抑制剂是恢复受辐射的GBM免疫原性的一种新方法。

PROJECT SUMMARY Glioblastoma (GBM) is a devastating brain tumor disease with a median overall survival of approximately 15 months. GBM patients die because of the constant ability of GBM to acquire resistance mechanisms against anti-cancer therapies, therefore leading to an inevitable tumor recurrence. Radiation therapy (RT) is a pivotal modality for improving overall survival of GBM. However, GBM invariably recurs, which suggests that RT is eliciting or exacerbating mechanisms of resistance in GBM. Identifying and overcoming the contributing factors involved in GBM resistance is a major challenge in Radiation Oncology. GBM metabolism and its role in immune evasion emerges as a RT-induced resistance mechanism in GBM. Specifically, we have preliminary data indicating that irradiated GBM cells reprogram their metabolism towards the generation of fatty acids. Such metabolic reprogramming after RT is impairing the innate immune recognition and systemic anti-tumor immunity elicited by RT. More precisely, we have preliminary evidence that fatty acid synthesis is inhibiting nucleic acid sensing-dependent interferon type I (IFN-I) responses and is promoting immunosuppressive signals such as the programmed-death-1 (PD-1) and the programmed-death ligand 1 (PD-L1). As a consequence, cancer cell-intrinsic IFN-I will not be released in response to RT. This ultimately limits anti-tumor immune response against GBM by precluding infiltration effector T cells into the GBM microenvironment. We have recently demonstrated that cancer cell-intrinsic IFN-I response is an essential step to convey immunogenicity of an irradiated tumor. Consequently, by increasing energy supply, limiting innate immunity and increasing immunosuppression, RT-induced fatty acid synthesis is likely to be a major GBM resistance mechanism that not only impacts RT response of GBM but also provides means to evade immune recognition. In this application, we propose to test the novel and innovative hypothesis that fatty acid metabolism induced by RT controls immune escape and GBM survival. Successful completion of this proposal will define how fatty acid synthesis facilitates GBM immune evasion and provide pre-clinical evidence for fatty acid inhibitors as a novel approach to restore the immunogenicity of irradiated GBM.