Immunometabolism in Cancer and Inflammation

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密切接触。因此，被免疫细胞浸润的肿瘤将有不同的代谢燃料的可用性，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。结合详细的生化分析、代谢组学、特异性抑制剂、通量分析和NCI-Frederick光学显微镜分析实验室的高清显微镜，我们发现腹膜常驻巨噬细胞（pRes）利用了效应功能的利基。腹膜生态位中的这种共生生化相互作用使我们研究了腹膜中对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多个例子。首先，我们发现腹膜间隙的癌症导致常驻腹膜巨噬细胞表达免疫应答基因-1 (Irg1)，积累衣康酸，并以Irg1依赖的方式促进肿瘤生长。因此，我们发现来自晚期癌症患者腹水的髓样细胞表达Irg1。在另一个例子中，我们发现来自患癌小鼠的中性粒细胞调整其代谢以利用葡萄糖耗尽的肿瘤微环境。这种适应性使它们能够抑制T细胞的功能，即使控制性中性粒细胞不能。在人类身上也有这种机制的迹象。乳腺癌患者外周血中具有这些代谢特征的中性粒细胞数量较多。除了对癌症的直接研究外，我们还确定了一氧化氮（NO）在巨噬细胞激活过程中代谢重编程中的作用。尽管这一机制在很大程度上被忽视了，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个关键代谢物，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，作为我们对代谢生态位的兴趣的一部分，我们发现巨噬细胞和腹腔灌洗液的体内特征与我们在体外研究中预测的一致。综上所述，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，还可以通过改变代谢生态位的组成来潜在地发挥代谢作用。正在进行的工作将更深入地探索NO和衣康酸在各种生理系统中的代谢作用，深入研究TME的肿瘤免疫串扰，并确定衣康酸产生的新来源和生物学。

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.