权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

摘要使用设计用于靶向肿瘤介导的免疫检查点抑制剂的最新进展免疫耐受已经彻底改变了癌症治疗。不幸的是，这些临床成功还没有转化为胶质母细胞瘤（GBM），这仍然是一种致命的恶性肿瘤治疗方案有限该领域的主要思想之一是解释这种缺乏在GBM中的临床益处是这些药剂作用于错误的靶点。肿瘤相关巨噬细胞（TAM）似乎代表了主要的免疫细胞， GBM中的免疫抑制微环境，数量大大超过T细胞浸润。因此，我们认为，人们对开发针对M2 TAMs或M2 TAMs的治疗策略有相当大的兴趣逆转其极化以增强抗肿瘤免疫力。我们发现了喹啉酸（QA），色氨酸代谢的下游中间体，作为先前的 GBM中未描述的代谢结节。通过一系列的调查，我们继续证明了QA通过极化来塑造GBM免疫景观的强大能力，巨噬细胞对免疫抑制M2表型的影响。有效的抗肿瘤活性是在颅内生长的GBM系中进行测试时观察到，支持了的治疗潜力靶向GBM中的QA代谢。在这一建议中，我们现在寻求确定机制，有助于QA介导的巨噬细胞极化（目标1），扩展研究评估 GBM中靶向QA的免疫/代谢后果（目的2），并确定合理的旨在利用抑制QA诱导的免疫抑制的组合策略（Aim 3）。如果成功，这些结果将提供一个以前未被识别的窗口， GBM微环境中肿瘤和免疫细胞之间的代谢相互作用，其功能免疫抑制的后果，以及鉴定新治疗药物的框架这种侵袭性恶性肿瘤的治疗策略有限。