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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010300-22
Application #
10014341
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
22
Fiscal Year
2019
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Tong, Wing-Hang; Maio, Nunziata; Zhang, De-Liang et al. (2018) TLR-activated repression of Fe-S cluster biogenesis drives a metabolic shift and alters histone and tubulin acetylation. Blood Adv 2:1146-1156
Davies, Luke C; Rice, Christopher M; Palmieri, Erika M et al. (2017) Peritoneal tissue-resident macrophages are metabolically poised to engage microbes using tissue-niche fuels. Nat Commun 8:2074
Palmieri, Erika M; Menga, Alessio; Martín-Pérez, Rosa et al. (2017) Pharmacologic or Genetic Targeting of Glutamine Synthetase Skews Macrophages toward an M1-like Phenotype and Inhibits Tumor Metastasis. Cell Rep 20:1654-1666
Burg, Ashley R; Quigley, Laura; Jones, Adam V et al. (2016) Orally administered ?-glucan attenuates the Th2 response in a model of airway hypersensitivity. Springerplus 5:815
Baseler, Walter A; Davies, Luke C; Quigley, Laura et al. (2016) Autocrine IL-10 functions as a rheostat for M1 macrophage glycolytic commitment by tuning nitric oxide production. Redox Biol 10:12-23
De Ravin, Suk See; Wu, Xiaolin; Moir, Susan et al. (2016) Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med 8:335ra57
Ma, Chi; Kesarwala, Aparna H; Eggert, Tobias et al. (2016) NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature 531:253-7
Thomas, Douglas D; Heinecke, Julie L; Ridnour, Lisa A et al. (2015) Signaling and stress: The redox landscape in NOS2 biology. Free Radic Biol Med 87:204-25
Shanker, Anil; Pellom Jr, Samuel T; Dudimah, Duafalia F et al. (2015) Bortezomib Improves Adoptive T-cell Therapy by Sensitizing Cancer Cells to FasL Cytotoxicity. Cancer Res 75:5260-72
Sen, Shurjo K; Boelte, Kimberly C; Barb, Jennifer J et al. (2014) Integrative DNA, RNA, and protein evidence connects TREML4 to coronary artery calcification. Am J Hum Genet 95:66-76

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