ZIA BC 010300 (ZIA) | |||
---|---|---|---|
Title | Signal Transduction of Paired Inhibitory Receptors of NK Cells and Macrophages | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | McVicar, Daniel | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $965,550 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) | Vascular Disease (10.0%) | ||
Research Type | |||
Normal Functioning Cancer Progression & Metastasis |
|||
Abstract | |||
The laboratory has been taking an approach that involves more consideration of the interactions within, and adaptations to, metabolic niches. We found that, compared to serum, the peritoneal niche is enriched in amino acid fuels, specifically glutamine and glutamate. 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) are relatively rich in mitochondria, and poised to use these fuels during inflammation. During stimulation, these cells engage succinate dehydrogenase (Complex II of the electron transport chain) using glutamine and glutamate as fuel, to generate reactive oxygen species directly via mitochondrial activity. This engagement is PKC-dependent and TLR-independent making it distinct from mechanisms of electron transport chain reconfigurations previously suggested. Our finding of a unique metabolic 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. As a result of this work, we propose substantial additional work on itaconate and Irg1. Our identification of niche specific metabolic adaptations prompted us to look for cancer niche adaptations of leukocytes. Models of cancer in mice are often accompanied by accumulation of myeloid cells that are sometimes referred to as myeloid-derived suppressor cells due to their ability to suppress T cell function in vitro and adaptive immunity in vivo. A prominent population of these cancer-associated myeloid cells are neutrophils. There are little data regarding neutrophil metabolic regulation so we first examined neutrophil metabolism across multiple niches. 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. |