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，与肿瘤细胞，基质细胞和血管结构紧密接触。结果，被免疫细胞浸润的肿瘤将具有不同的代谢燃料可用性，这些燃料会在生长过程中驱动肿瘤的适应性，反之亦然。我们最近发现，腹膜腔是独特的代谢生态位。使用详细的生化分析，代谢组学，特定抑制剂，通量分析和高清晰度显微镜与NCI-Frederick光学显微镜分析实验室的结合，我们发现腹膜驻留巨噬细胞（PRES）利用了该利基的效果功能。这种腹膜生态生物的这种共生生物化学相互作用使我们检查了对腹膜癌症的代谢适应性。简而言之，我们发现了癌症中这种关系的多个例子。首先，我们在腹膜空间中发现癌症会导致居民腹膜巨噬细胞表达免疫响应基因-1（IRG1），积累伊卡醛酸，并以IRG1依赖性方式促进肿瘤生长。因此，我们发现来自晚期癌症患者腹水的髓样细胞表达了IRG1。在另一个例子中，我们发现来自癌症小鼠的中性粒细胞适应其新陈代谢，以利用葡萄糖耗尽的肿瘤微环境。这种适应使他们即使对照中性粒细胞不能抑制T细胞功能。在这里再次有迹象表明人类这种机制。乳腺癌患者的外周血具有更多具有这些代谢特征的中性粒细胞。除了直接研究癌症外，我们还定义了一氧化氮（NO）在巨噬细胞激活期间发生的代谢重编程中的作用。尽管这种机制在很大程度上被忽略了，但我们发现这些细胞的几种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产物，包括伊龙酸盐，柠檬酸盐，α-酮戊二酸酯和琥珀酸酯。重要的是，作为我们对代谢生态位的兴趣的一部分，我们发现巨噬细胞的体内特征和腹膜灌洗液与我们的体外研究预测的液体相匹配。综上所述，我们的工作证明了先天免疫细胞不仅可以适应其代谢组合，而且通过改变代谢生态裂的组成而在反式中产生代谢作用的强大能力。正在进行的工作更深入地探讨了在多种生理系统中NO和Itaconate的代谢作用，并深入研究了TME的肿瘤免疫串扰，并定义了与Itaconate产生相关的新来源和生物学。