Immunometabolism in Cancer and Inflammation

癌症和炎症中的免疫代谢

• 批准号: 10262060
• 负责人: Daniel W. McVicar
• 金额: $ 185.35万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10262060
• 关键词: 2019-nCoV; Acids; Advanced Malignant Neoplasm; Affect; Animal Model; Anti-Inflammatory Agents; Antiinflammatory Effect; Ascites; Biochemical; Breast Cancer Patient; COVID-19; Cancer Patient; Cell physiology; Cells; Characteristics; Chloroquine; Citrates; Development; Disease; Disease Outbreaks; Drug Kinetics; Environment; Epithelial Cells; Genes; Glucose; Goals; Greater sac of peritoneum; Growth; Human; Immune; Immunologics; In Vitro; Infection; Inflammation; Ionophores; Laboratories; Leukocytes; Liquid substance; Lung; Macrophage Activation; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Metabolic; Metabolic Pathway; Metabolism; Microscopy; Modification; Molecular Biology; Monitor; Mus; Myeloid Cells; Nitric Oxide; Optics; Peritoneal; Peritoneal Macrophages; Peritoneal lavage; Peritoneum; Physiological; Production; RNA Viruses; RNA-Directed RNA Polymerase; Reporting; Role; Succinates; System; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Virus Replication; Work; Zinc Chloride; alpha ketoglutarate; detector; immunological status; in vivo; inhibitor/antagonist; interest; macrophage; metabolomics; mouse model; neutrophil; peripheral blood; response; systemic toxicity; therapeutic target; tumor; tumor growth; tumor microenvironment; tumor progression

The laboratory has been taking an approach that involves more consideration of the interactions within, and adaptations to, metabolic niches. We hypothesize that metabolic adaptation of immune cells results in modification of their environment. As a consequence, tumors infiltrated with immune cells will have different availability of metabolic fuels that will drive adaptation of tumors during growth and vice versa. We recently found that the peritoneal cavity is a unique metabolic niche. Using a combination of detailed biochemical analysis, metabolomics, specific inhibitors, flux analysis, and high definition microscopy with the NCI-Frederick Optical Microscopy Analysis Laboratory we found that peritoneal resident macrophages (pRes) exploit that niche for effector function. This symbiotic biochemical interaction in the peritoneal niche led us to examine possible metabolic adaptation to cancer in the peritoneum. In brief, we found two examples of that relationship in cancer. In the first, we found cancer in the peritoneal space causes resident peritoneal macrophages to express Immunoresponsive Gene-1 (Irg1), accumulate itaconic acid, and promote tumor growth in an Irg1-dependent manner. Accordingly, we found that myeloid cells from the ascites of advanced cancer patients expressed Irg1. In the second example, we found that neutrophils from cancer bearing mice adapt their metabolism in order to exploit the glucose depleted tumor microenvironment. This adaptation permits them to suppress T cell function even when control neutrophils cannot. Here again there were indications of this mechanism in humans. Peripheral blood of breast cancer patients had greater numbers of neutrophils with these metabolic characteristics. In addition to direct studies of cancer, we have defined the role of nitric oxide (NO) in the metabolic reprogramming that occurs during macrophage activation. Although this mechanism has been largely overlooked, we found that several of the metabolic characteristics of these cells are solely due to the production of NO. The profound effects of NO on the metabolic adaptations of these cells includes control of several key metabolites including itaconate, citrate, alpha-ketoglutarate, and succinate. Importantly, as part of our interest in the metabolic niche, we find that in vivo signatures of macrophages and in peritoneal lavage fluid match those predicted by our in vitro studies. Taken together our work demonstrates the powerful ability of innate immune cells to not only adapt their metabolic portfolios but to potentially exert metabolic effects in trans by altering the composition of the metabolic niche. Ongoing work more deeply explores the metabolic effects of NO and itaconate in a variety of physiological systems. In response to the recent outbreak of SARS-CoV-2 we have begun to investigate the potential therapeutic efficacy of Chloroquine in combination with Zn2+. Chloroquine is known to have anti-inflammatory effects. Recently, it has been shown that Chloroquine is an effective Zn2+ ionophore in vitro. Zn2+ is a known inhibitor of the RNA-dependent RNA polymerase (RdRp) used by RNA viruses such as SARS-CoV-2. This raises the intriguing possibility that Chloroquine may be beneficial in COVID-19 disease through two mechanisms; anti-inflammatory and suppression of viral replication via Zn2+-mediated suppression of RdRp. Given the reported toxicity of Chloroquine we hypothesized that local, intranasal application in combination with ZnCl2 might substantially increase Zn2+ levels in lung epithelial cells while limiting systemic toxicity. We are testing this hypothesis by using mouse models, Zn2+ detectors and mass spectroscopy to monitor Zn2+ levels in lung leukocytes and epithelial cells and Chloroquine pharmacokinetics.

该实验室一直在采取一种方法，更多地考虑代谢生态位内的相互作用和适应。我们假设免疫细胞的代谢适应会导致其环境的改变。因此，浸润有免疫细胞的肿瘤将具有不同的代谢燃料可用性，这将推动肿瘤在生长过程中的适应，反之亦然。我们最近发现腹膜腔是一个独特的代谢生态位。通过将详细的生化分析、代谢组学、特异性抑制剂、通量分析和高清显微镜与 NCI-Frederick 光学显微镜分析实验室相结合，我们发现腹膜驻留巨噬细胞 (pRes) 利用该利基来发挥效应功能。腹膜生态位中的这种共生生化相互作用使我们检查腹膜中癌症可能的代谢适应。简而言之，我们在癌症中发现了这种关系的两个例子。首先，我们发现腹膜腔中的癌症会导致腹膜巨噬细胞表达免疫反应基因 1 (Irg1)，积累衣康酸，并以 Irg1 依赖性方式促进肿瘤生长。因此，我们发现晚期癌症患者腹水中的骨髓细胞表达 Irg1。在第二个例子中，我们发现来自患有癌症的小鼠的中性粒细胞调整其新陈代谢，以利用葡萄糖耗尽的肿瘤微环境。这种适应使它们能够抑制 T 细胞功能，即使控制中性粒细胞不能抑制 T 细胞功能。这里再次有迹象表明人类存在这种机制。乳腺癌患者的外周血中具有更多具有这些代谢特征的中性粒细胞。除了对癌症的直接研究之外，我们还定义了一氧化氮 (NO) 在巨噬细胞激活过程中发生的代谢重编程中的作用。尽管这一机制在很大程度上被忽视，但我们发现这些细胞的一些代谢特征完全是由于 NO 的产生。 NO 对这些细胞代谢适应的深远影响包括控制几种关键代谢物，包括衣康酸、柠檬酸、α-酮戊二酸和琥珀酸。重要的是，作为我们对代谢生态位兴趣的一部分，我们发现巨噬细胞和腹腔灌洗液的体内特征与我们体外研究预测的一致。总而言之，我们的工作证明了先天免疫细胞的强大能力，不仅可以调整其代谢组合，而且可以通过改变代谢生态位的组成来潜在地发挥反式代谢效应。正在进行的工作更深入地探索一氧化氮和衣康酸在各种生理系统中的代谢作用。为了应对最近爆发的 SARS-CoV-2，我们已开始研究氯喹与 Zn2+ 联合使用的潜在治疗功效。已知氯喹具有抗炎作用。最近，研究表明氯喹在体外是一种有效的 Zn2+ 离子载体。 Zn2+ 是一种已知的 RNA 依赖性 RNA 聚合酶 (RdRp) 抑制剂，该酶被 SARS-CoV-2 等 RNA 病毒使用。这提出了一种有趣的可能性，即氯喹可能通过两种机制对 COVID-19 疾病有益；通过 Zn2+ 介导的 RdRp 抑制来抗炎和抑制病毒复制。鉴于报道的氯喹毒性，我们假设局部鼻内应用与 ZnCl2 组合可能会显着增加肺上皮细胞中 Zn2+ 的水平，同时限制全身毒性。我们正在通过使用小鼠模型、Zn2+探测器和质谱来监测肺白细胞和上皮细胞中的Zn2+水平以及氯喹药代动力学来测试这一假设。