Immunometabolism in Cancer and Inflammation

癌症和炎症中的免疫代谢

• 批准号: 10702328
• 负责人: Daniel W. McVicar
• 金额: $ 196.39万
• 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/10702328
• 关键词: Acids; Advanced Malignant Neoplasm; Affect; Animal Model; Architecture; Ascites; Biochemical; Biology; Blood Vessels; Breast Cancer Patient; Cancer Patient; Cell physiology; Cells; Characteristics; Citrates; Complex; Development; Genes; Glucose; Goals; Greater sac of peritoneum; Growth; Human; Immune; Immunologics; In Vitro; Infection; Inflammation; Laboratories; Liquid substance; Macrophage Activation; Malignant Neoplasms; Metabolic; Metabolic Pathway; Metabolism; Microscopy; Molecular Biology; Mus; Myeloid Cells; Nitric Oxide; Optics; Peritoneal; Peritoneal Macrophages; Peritoneal lavage; Peritoneum; Physiological; Production; Role; Source; Stromal Cells; Succinates; System; T-Lymphocyte; Therapeutic; Work; alpha ketoglutarate; immunological status; in vivo; inhibitor; interest; macrophage; metabolomics; neoplastic cell; neutrophil; peripheral blood; response; therapeutic target; tumor; tumor growth; tumor microenvironment; tumor progression

In cancer immune cells exist in a complex tumor microenvironment in close contact with tumor cells, stromal cells, and vascular architecture. 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 multiple 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 another 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, delves into the tumor-immune crosstalk of the TME, and defines new sources and biology associated with the production of itaconate.

在癌症中，免疫细胞存在于复杂的肿瘤微环境中， 肿瘤细胞、基质细胞和血管结构。结果，肿瘤浸润了 与免疫细胞将有不同的代谢燃料， 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。结合详细的生化分析， 代谢组学，特异性抑制剂，通量分析和高清晰度显微镜， NCI-Frederick光学显微镜分析实验室发现， 巨噬细胞（pRes）利用小生境发挥效应子功能。这种共生的生化物质 腹膜小生境中的相互作用使我们研究了可能的代谢适应癌症 在腹膜里。简而言之，我们在癌症中发现了这种关系的多个例子。在 首先，我们发现腹腔内的癌症会导致腹膜内的巨噬细胞， 表达免疫应答基因-1（Irg 1），积累衣康酸，促进肿瘤生长， irg 1依赖性的方式。因此，我们发现，从腹水中提取的髓系细胞 晚期癌症患者表达Irg 1。在另一个例子中，我们发现， 携带癌症的小鼠调整它们的代谢以利用葡萄糖耗尽的肿瘤 微环境这种适应允许他们抑制T细胞功能，即使在控制 中性粒细胞则不能。这里再次有迹象表明这种机制在人类身上。外围 乳腺癌患者的血液中有更多的中性粒细胞， 特色除了对癌症的直接研究，我们还确定了一氧化氮的作用， 在巨噬细胞活化过程中发生的代谢重编程中的氧化物（NO）。虽然 这种机制在很大程度上被忽视了，我们发现，一些代谢 这些细胞的特性完全是由于NO的产生。 NO对这些细胞代谢适应的影响包括对几种关键代谢产物的控制 包括衣康酸盐、柠檬酸盐、α-酮戊二酸盐和琥珀酸盐。重要的是，作为我们 在代谢生态位的兴趣，我们发现，在体内签名的巨噬细胞和 腹腔灌洗液与我们体外研究预测的结果相符。综合我们的工作 证明了先天免疫细胞的强大能力，不仅适应他们的代谢， 投资组合，但潜在地发挥代谢作用，在反式通过改变的组成， 代谢生态位正在进行的工作更深入地探讨了NO的代谢作用， 衣康酸盐在各种生理系统中的作用，深入研究了肿瘤免疫串扰， TME，并定义了与生产相关的新来源和生物学。 衣康酸盐。