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

脂肪酸代谢调节抗辐射胶质母细胞瘤的免疫

基本信息

批准号：
10638744
负责人：
Claire Isabelle Vanpouille-Box
金额：
$ 58.74万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10638744
关键词：
Abscopal effect Acute Adult Brain Brain Neoplasms CD8-Positive T-Lymphocytes CD8B1 gene Cell physiology Cells Coculture Techniques Color Cyclic GMP Cytotoxic T-Lymphocytes Data Data Set Disease Effector Cell Energy Supply FDA approved Fatty Acid Desaturases Fatty Acids Fatty-acid synthase Flow Cytometry Generations Genes Glioblastoma Goals Growth Human Immune Immune Evasion Immune response Immune system Immunity Immunologic Stimulation Immunosuppression Impairment Infiltration Interferon Type I Irradiated tumor Knowledge Malignant Neoplasms Mediating Metabolic Metabolism Modality Modeling Mus Natural Immunity Nucleic Acids Patients Phenotype Process Production Proliferating Property Proteins Radiation Radiation Oncology Radiation therapy Recurrence Recurrent tumor Regulation Regulatory T-Lymphocyte Research Resistance Role Signal Transduction Slice T cell infiltration T-Cell Activation T-Lymphocyte Testing Therapeutic Time Treatment Efficacy Tretinoin Tumor Immunity Up-Regulation VEGFA gene anti-tumor immune response cancer cell cancer therapy cytotoxic CD8 T cells effective therapy effector T cell fatty acid biosynthesis fatty acid metabolism immunogenic immunogenicity improved in vitro testing in vivo inhibitor innovation lipid metabolism melanoma novel novel strategies novel therapeutics overexpression patient derived xenograft model pharmacologic pre-clinical prevent programmed cell death ligand 1 programmed cell death protein 1 programs radiation response recruit resistance mechanism response sensor standard of care synergism temozolomide treatment response tumor tumor-immune system interactions

项目摘要

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.

项目概要胶质母细胞瘤 (GBM) 是一种毁灭性的脑肿瘤疾病，中位总生存期约为 15 几个月。 GBM 患者因 GBM 持续获得抵抗机制的能力而死亡抗癌治疗，因此导致不可避免的肿瘤复发。放射治疗（RT）是改善 GBM 总体生存率的关键方法。然而，GBM 总是复发，这表明放疗正在引发或加剧 GBM 的耐药机制。识别和克服 GBM 耐药性的影响因素是放射治疗领域的一项重大挑战肿瘤学。 GBM 代谢及其在免疫逃避中的作用作为 RT 诱导的抵抗机制出现在GBM中。具体来说，我们的初步数据表明，受辐射的 GBM 细胞会重新编程其新陈代谢促进脂肪酸的生成。放疗后的这种代谢重编程正在损害先天免疫 RT 引起的识别和全身抗肿瘤免疫。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性干扰素 I 型 (IFN-I) 反应，并且促进免疫抑制信号，例如程序性死亡-1 (PD-1) 和程序性死亡配体 1 (PD-L1)。因此，癌细胞固有的 IFN-I 不会因放疗而释放。这通过阻止效应 T 细胞浸润到 GBM，最终限制针对 GBM 的抗肿瘤免疫反应微环境。我们最近证明癌细胞内在的 IFN-I 反应是一个重要的步骤传达受辐射肿瘤的免疫原性。因此，通过增加能量供应，限制先天免疫和增加免疫抑制，RT 诱导的脂肪酸合成可能是主要的 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认出。在此应用中，我们建议测试脂肪酸的新颖且创新的假设 RT 诱导的代谢控制免疫逃逸和 GBM 存活。顺利完成本次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研究脂肪酸抑制剂作为恢复受辐射 GBM 免疫原性的新方法的证据。