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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.

项目总结