Immunometabolism in Cancer and Inflammation

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

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.