Immunometabolism in Cancer and Inflammation

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

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.