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 that clodronate depletion of pRes reproducibly reduced tumor burden in the peritoneum. Metabolic assessment showed that pRes from peritoneal tumor-bearing mice had higher levels of fatty acid driven oxygen consumption, and accumulated itaconic acid produced by the enzyme Immunoresponsive Gene-1 (Irg1). Remarkably, specific knockdown of Irg1 only in pRes, was sufficient to ablate their pro-tumor effects. We mechanistically dissected this activity and found that Irg1 expression facilitated oxidative phosphorylation of fatty acids resulting in ROS formation which in turn activates pErk in tumor cells. Our data suggest that the tumor niche in the peritoneum elicits Irg1 resulting in metabolic reprogramming into a tumor promotion state. Our identification of niche specific cancer-associated metabolic adaptations prompted us to look for cancer niche adaptations of leukocytes. We uncovered a subpopulation of cKit-dependent neutrophils with higher levels of mitochondrial function and the unique ability to generate substantial oxidative burst even when glucose utilization was limited. Breast cancer-associated (4T1) neutrophils have these same characteristics. We mapped these characteristics to the ability to utilize fatty acids for the generation of NADPH, that in turn fuels Nox2. Importantly, the peripheral blood of cancer patients also showed increased numbers of neutrophils with an immature phenotype that were higher in mitochondrial content than controls, and had higher levels of oxygen consumption. Most recently, we have confirmed using model of parasitic infection and endotoxic shock, that specific metabolic reprogramming driven by IL4 or nitric oxide, respectively, results in substantial modification of the overall peritoneal niche. These findings, confirm our hypothesis by revealing that immune cell metabolic programming can have wide ranging physiologic effects by controlling the metabolic fuels available to surrounding cells.
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