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.

项目摘要肿瘤相关的髓样细胞（TAMC），由肿瘤相关的巨噬细胞和髓样组成衍生的抑制细胞构成了神经胶质瘤中大多数细胞浸润。 TAMC有效免疫抑制作用，代表了成功免疫疗法的主要障碍。 TAMCS高度表达精氨酸酶-1（Arg-1），一种被认为是从肿瘤微环境中耗尽精氨酸的分解代谢酶。尽管作为免疫抑制细胞的众所周知的标记，这种选择的代谢原因尚不清楚。使用RNA-Seq，Bulk代谢组学和碳-13精氨酸通量显示，精氨酸分解代谢的两种单独的途径在一代中融合鸟氨酸。鸟氨酸是多胺的脱诺沃生成的先决条件，一组氮丰富的代谢产物对生物学的所有领域具有基本重要性。重要的是，我们发现速率 - 多胺产生的限制步骤，鸟氨酸脱羧酶1（ODC1）被神经胶质瘤急剧上调浸润TAMC，表明De-Novo多胺产生对其功能很重要。因此，该提案的总体目标是确定如何通过TAMC将精氨酸分解为多胺，以及确定抑制这种代谢途径是否可以增强神经胶质瘤的免疫疗法。有趣的是，我们发现精氨酸代谢的第二个未研究的代谢途径， taMCS在我们的神经胶质瘤模型中优先利用了鸟氨酸的肌酸的新肌酸。第一个目标这个项目的是生成基因工程的小鼠（GEM）来确定De-Novo肌酸的作用在胶质母细胞瘤小鼠模型中产生免疫抑制的代谢。如果肌酸，这个目标将剖析生成被用作在脑肿瘤中生存的燃料，或用于促进免疫抑制。我们的初步实验表明，抑制精氨酸代谢，多胺，可以扰动TAMC免疫抑制。这表明多胺可能是关键的代谢物 TAMC在脑肿瘤中的功能。因此，该提案的第二个目的是调查 TAMC在神经胶质瘤中的多胺代谢。我们将生成独特的条件淘汰动物模型探测该途径在神经胶质瘤中TAMC的免疫抑制功能中的重要性。该项目的第三个目的是确定这些途径的靶向是否可以与标准结合在一起护理胶质瘤促进动物生存。首先，我们将测试是否是血脑屏障的可渗透抑制剂肌酸激酶可用于在神经胶质瘤中阻碍TAMC。接下来，我们将使用良好的多胺抑制剂生成和多胺摄取试图钝化TAMC介导的神经胶质瘤中的免疫抑制。最后，我们将采用上述临床抑制剂，并确定它们是否可以用于增强检查点神经胶质瘤的免疫疗法。