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Quinolinate-induced immune suppression in glioblastoma

喹啉诱导的胶质母细胞瘤免疫抑制

基本信息

批准号：
10735763
负责人：
Prakash Chinnaiyan
金额：
$ 38万
依托单位：
WILLIAM BEAUMONT HOSPITAL RESEARCH INST
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：
2023-08-15 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735763
关键词：
Alzheimer&apos s Disease Biological Brain Cells Clinical Complex Coupling Data FOXO1A gene Genetically Engineered Mouse Genomics Glioblastoma Glioma Human Immune Immune Tolerance Immune checkpoint inhibitor Immunologics Immunosuppression Investigation Laboratory Study Macrophage Malignant Neoplasms Mediating Memantine Metabolic Metabolic Pathway Metabolism Microglia Modeling Mus Neurodegenerative Disorders Neurosciences Research Outcome Parkinson Disease Pathway interactions Patients Peripheral Phenotype Play Pre-Clinical Model Production Property Radiation Research Design Role Sampling Series Signal Transduction T cell infiltration T-Lymphocyte Testing Therapeutic Thinking Treatment Protocols Tryptophan Metabolism Pathway Tumor Immunity Tumor-associated macrophages Work aggressive therapy cancer therapy combinatorial design immune checkpoint in vivo inhibitor interest metabolomics model design molecular phenotype monocyte neoplastic cell next generation novel novel strategies novel therapeutic intervention quinolinate radiation response receptor response success tumor tumor metabolism

项目摘要

ABSTRACT Recent advancements using immune checkpoint inhibitors designed to target tumor-mediated immune tolerance have revolutionized cancer therapy. Unfortunately, these clinical successes have not translated to glioblastoma (GBM), which continues to be an invariably fatal malignancy with limited treatment options. One of the leading thoughts in the field explaining this lack of clinical benefit in GBM is that these agents are acting upon the wrong target. Tumor-associated macrophages (TAMs) appear to represent the primary immune cells contributing towards the immune suppressive microenvironment in GBM, vastly outnumbering T cell infiltration. Hence, there is considerable interest in developing therapeutic strategies designed to target M2 TAMs or revert their polarization to enhance antitumor immunity. We discovered the accumulation of quinolinate (QA), a downstream intermediate of tryptophan metabolism, as a previously undescribed metabolic node in GBM. Through a series of investigations, we went on to demonstrate the potent ability of QA to sculpt the GBM immune landscape by polarizing macrophages towards the immune suppressive M2 phenotype. Potent anti-tumor activity was observed when tested in GBM lines grown intracranially, supporting the therapeutic potential of targeting QA metabolism in GBM. In this proposal, we now seek to define mechanisms contributing towards QA-mediated macrophage polarization (Aim 1), extend studies evaluating the immunologic/metabolic consequence of targeting QA in GBM (Aim 2), and identify rational combinatorial strategies designed to exploit inhibition of QA-induced immune suppression (Aim 3). If successful, these results would offer a previously unrecognized window into the complex metabolic interplay between tumor and immune cells in the GBM microenvironment, its functional consequence on immune suppression, and framework for the identification of novel therapeutic strategies in this aggressive malignancy with limited treatment options.

摘要