Arginine Metabolism Regulates Myeloid Immune Suppression in Glioblastoma

精氨酸代谢调节胶质母细胞瘤的骨髓免疫抑制

基本信息

批准号：
10554277
负责人：
MACIEJ S LESNIAK
金额：
$ 37.6万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10554277
关键词：
Adipocytes Anabolism Animal Model Animals Antitumor Response Arginine Basic Science Biology Brain Brain Neoplasms Carbon Catabolism Cell Survival Cell physiology Cells Clinical Communication Consumption Creatine Creatine Kinase Data Effectiveness Enzymes Generations Genetic Genetically Engineered Mouse Glioblastoma Glioma Goals Growth Hypoxia Immune Immune Cell Suppression Immunosuppression Immunotherapy Infiltration Laboratories Macrophage Maintenance Malignant Neoplasms Malignant neoplasm of brain Mediating Metabolic Metabolic Pathway Metabolism Modeling Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Nitrogen Ornithine Ornithine Decarboxylase Ovary Pathway interactions Phenotype Plants Polyamines Reporting Role Signal Transduction Site T cell infiltration T-Lymphocyte Testing Testis Tumor Immunity Tumor-associated macrophages Vascularization Work anti-PD-1 arginase blood-brain barrier permeabilization cancer infiltrating T cells checkpoint therapy clinically relevant conditional knockout experimental study improved inhibitor knockout animal metabolomics mouse model pharmacologic preference prevent standard of care synergism therapeutic target transcriptome sequencing translational approach tumor tumor growth tumor metabolism tumor microenvironment uptake

项目摘要

PROJECT SUMMARY Tumor-associated myeloid cells (TAMCs), which consist of tumor associated macrophages and myeloid- derived suppressor cells, make up a majority of cellular infiltrates in glioma. TAMCs are potently immunosuppressive, and represent a major barrier to successful immunotherapy. TAMCs highly express arginase-1 (Arg-1), a catabolic enzyme thought to deplete arginine from the tumor microenvironment. Despite being a well-known marker of immunosuppressive cells, the metabolic reasons for this choice are not clear. Examination of TAMCs phenotype in murine glioma models using RNA-seq, bulk metabolomics, and carbon-13 arginine flux revealed that two separate pathways of arginine catabolism converge on the generation of ornithine. Ornithine is the prerequisite substrate for the de-novo generation of polyamines, a group of nitrogen- rich metabolites with foundational importance to all domains of biology. Importantly, we found that the rate- limiting step of polyamine generation, ornithine decarboxylase 1 (ODC1), is dramatically upregulated by glioma infiltrating TAMCS, suggesting de-novo polyamine generation is important for their function. Therefore, the overall goal of this proposal is to determine how arginine is catabolized into polyamines by TAMCs, and to determine if inhibition of this metabolic pathway can enhance immunotherapy for glioma. Interestingly, we discovered that a second, unstudied metabolic pathway of arginine metabolism, the de- novo generation of creatine from ornithine, is preferentially utilized by TAMCs in our glioma models. The first aim of this project is to generate genetically engineered mice (GEM) to determine the role of the de-novo creatine metabolism in generating immunosuppression in mouse models of glioblastoma. This aim will dissect if creatine generation is used as a fuel to survive in brain tumors, or is being used to promote immunosuppression. Our preliminary experiments suggest that inhibition of the products of arginine metabolism, polyamines, can perturb TAMC immune suppression. This suggests that polyamines may be critical metabolites for the functions of TAMCs in brain tumors. Therefore, the second aim of this proposal is to probe the importance of polyamine metabolism by TAMCs in glioma. We will generate unique conditional knockout animal models to probe the importance of this pathway in the immunosuppressive functions of TAMCs in glioma. The third aim of this project is to determine if targeting of these pathways can be combined with standard of care for glioma to promote animal survival. First, we will test if a blood-brain-barrier permeable inhibitor of creatine kinase can be used to stymie TAMCs in glioma. Next, we will use well established inhibitors of polyamine generation and polyamine uptake in attempts to blunt TAMC mediated immunosuppression in glioma. Lastly, we will take the clinical inhibitors described above, and determine if they can be used to potentiate checkpoint immunotherapy for glioma.

项目概要肿瘤相关骨髓细胞 (TAMC)，由肿瘤相关巨噬细胞和骨髓细胞组成衍生的抑制细胞构成神经胶质瘤细胞浸润的大部分。 TAMC 具有强大的免疫抑制，是成功免疫治疗的主要障碍。 TAMCs高表达精氨酸酶-1 (Arg-1)，一种分解代谢酶，被认为可以消耗肿瘤微环境中的精氨酸。尽管作为免疫抑制细胞的众所周知的标志物，这种选择的代谢原因尚不清楚。使用 RNA-seq、本体代谢组学和方法检查小鼠神经胶质瘤模型中的 TAMC 表型碳-13精氨酸通量揭示了精氨酸分解代谢的两条独立途径在一代上汇聚鸟氨酸。鸟氨酸是从头生成多胺的先决底物，多胺是一组氮- 丰富的代谢物对生物学的所有领域都具有基础重要性。重要的是，我们发现该比率- 多胺生成的限制步骤鸟氨酸脱羧酶 1 (ODC1) 受到神经胶质瘤的显着上调渗透 TMCS，表明从头生成多胺对其功能很重要。因此，该提案的总体目标是确定精氨酸如何被 TAMC 分解代谢为多胺，并确定抑制该代谢途径是否可以增强神经胶质瘤的免疫治疗。有趣的是，我们发现精氨酸代谢的第二种未经研究的代谢途径，即在我们的神经胶质瘤模型中，TAMC 优先利用鸟氨酸重新生成肌酸。第一个目标该项目的目的是培育基因工程小鼠 (GEM) 以确定从头肌酸的作用胶质母细胞瘤小鼠模型中产生免疫抑制的代谢。这个目标将剖析肌酸是否生成被用作脑肿瘤生存的燃料，或被用来促进免疫抑制。我们的初步实验表明，抑制精氨酸代谢产物、多胺、可以干扰 TAMC 免疫抑制。这表明多胺可能是 TAMCs 在脑肿瘤中的功能。因此，本提案的第二个目的是探讨神经胶质瘤中 TAMC 的多胺代谢。我们将生成独特的条件敲除动物模型探讨该通路在胶质瘤 TAMC 免疫抑制功能中的重要性。该项目的第三个目标是确定这些途径的靶向是否可以与标准相结合护理神经胶质瘤以促进动物生存。首先，我们将测试血脑屏障渗透性抑制剂是否肌酸激酶可用于抑制神经胶质瘤中的 TAMC。接下来，我们将使用成熟的多胺抑制剂多胺的产生和摄取，试图减弱神经胶质瘤中 TAMC 介导的免疫抑制。最后，我们将采用上述临床抑制剂，并确定它们是否可用于增强检查点神经胶质瘤的免疫治疗。