Immunometabolism in Cancer and Inflammation

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

The tumor microenvironment represents a complex multicellular milieu where various cell types compete for the resources necessary for their function(s). Tumor cells promote the expansion of host vasculature to maintain sufficient levels of the nutrients required for their rapid proliferation. At the same time, tumor cells subjugate host defense mechanisms to thwart rejection. Many mechanisms of tumor-mediated immunosuppression have been described, and several target metabolic pathways. For example, highly glycolytic tumors deplete glucose in the microenvironment, suppressing T cell proliferation and activation. The resulting elevated lactate from the tumor can transcriptionally reprogram tumor-associated macrophages into immunosuppressive cells promoting tumor growth and progression. Taking these types of interactions into consideration, we view the tumor as a unique metabolic environment, or niche, within which the tumor cells and immune cells compete for resources and adapt to each other's presence. The aggressive nature of many cancers reflects the ability of tumors to exert a dominant role in this niche, subjugating the attempted immune response to facilitate tumor expansion, vascularization, and dissemination. This project is focused on understanding stimulation-induced alterations in cellular metabolic processes and the critical role that they play in enabling immune cells to meet the enhanced metabolic demands associated with activation. Thus, our work involves precise dissection of metabolic networks that govern immune cell function, as well as the investigation of the metabolic foundations of disease. Our work in this area has already provided us with exciting possibilities for unraveling, and possibly therapeutically exploiting, the substantial metabolic interactions between inflammatory cells and the tumor. In one aspect of this project, we found that a soluble version of Triggering Receptors Expressed on Myeloid cells (TREM)-1 is a biomarker in renal cancer. Our findings contribute to the role that the TREM family of receptors play in a variety of inflammatory diseases including cancer. Our work also defines the canonical role of pyruvate kinase muscle-2 (PKM2) in the metabolic control of Natural Killer (NK) cells and CD4+ T cells. As the penultimate enzyme of glycolysis, PKM converts phosphoenolpyruvate and ADP into ATP and pyruvate that is either fermented to lactate or imported into the mitochondria for oxidation. Our work has identified PKM2 as a central metabolic regulator of both NK and T cell function. In NK cells, the loss of PKM2 controlled cellular ROS levels and suppressed Myc signaling whereas in CD4+ T cells PKM2 controls pyruvate oxidation, and its absence leads to substantial oxidative cell death. These findings underscore the canonical function of PKM2 as a regulator of pyruvate utilization and contribute to the assignment of this metabolic pathway as a central regulator of NK and CD4+ T cell function. Our earlier work on the uniqueness of the peritoneal niche and its role in macrophage function, followed by our definition of neutrophil metabolic adaptations in cancer, have greatly refined our understanding on the metabolic adaptations that contribute to cancer progression in specific niches such as the peritoneal cavity. Our work in this project has identified cancers of the peritoneal cavity cause the upregulated expression of Immunoresponsive Gene-1 (Irg1) in resident macrophages and accumulation of itaconic acid. We found Irg-1 to promote tumors in part through an enhancement of lipid utilization. We found that myeloid cells from the ascites of advanced cancer patients expressed Irg1 and identify Irg-1 as an attractive therapeutic target, since abrogation of Irg-1 expression significantly reduced peritoneal tumor burden in mice. We have extended our work on Irg-1 in the tumor setting with additional dissection of the role of itaconate in macrophage physiology and lipid metabolism. We find that itaconate produced by macrophages in the liver during feeding with high fat diet (HFD), induces an increase in the lipid utilization of hepatocytes, resulting in better control of lipid adiposity. The livers of human non-alcoholic steatohepatitis (NASH) patients show increased expression of Irg-1 and have elevated levels of itaconate. Irg1-/- mice fed HFD have exacerbated liver adiposity and more pronounced metabolic disorder as revealed by worsened glucose and insulin tolerance. Mechanistically, itaconate exposure increases oxidative phosphorylation in hepatocytes by flux analysis, and 13C labeling shows greater amounts of palmitate utilization. We propose that itaconate activated to itaconyl-CoA suppresses substrate-level phosphorylation, reducing ATP levels leading to compensatory increases in lipid utilization. Our ongoing work seeks to extend our study of itaconate physiology and utilize models of tumor-associated macrophage development to define additional regulators of macrophage function in tumors. 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. 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. We had previously found that autologous NO was necessary and sufficient to drive the decline in oxidative phosphorylation associated with "glycolytic commitment". Using unbiased metabolomics, expression analysis, metabolic flux analysis, 13C carbon tracing experiments, and enzymology, we have extensively defined the role of NO in this metabolic reprogramming of macrophages. Our work on this project 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. Together, these findings define leukocyte metabolic enzymes as bona fide therapeutic targets and demonstrate the importance of understanding immunometabolism in the context of unique physiological niches relevant to cancer.