The goal of the Rathmell lab is to establish the regulation and role of metabolic pathways in lymphocyte activation, differentiation, and transformation. This work includes studies on both immunologic and cancer metabolism aiming to identify mechanisms by which cell metabolism modulates inflammatory diseases and anti-tumor immunity as well as growth and proliferation of cancer cells. To achieve this goal we have four main project areas.
1) We are examining the regulation of metabolism of T cell subsets. T lymphocytes are important to drive and control immunity and inflammation. We have shown that T cell activation in response to infection or autoimmunity leads to a dramatic metabolic reprogramming from oxidative metabolism that largely supports energy generation to a highly glycolytic metabolism that can promote biosynthesis and cell growth. If this metabolic reprogramming does not occur, T cells are unable to activate, grow, or function to control infection or cancer. Importantly, T cells also differentiate as activation progresses and we have found that different T cell subsets utilize distinct metabolic programs. The most inflammatory T cells become the most highly glycolytic, while the immune suppressive regulatory T cells (Treg) become least glycolytic and instead rely on mitochondrial oxidative pathways. The specific metabolic differences between these subsets may allow metabolic targeting or modulation in multiple inflammatory settings. We are now examining this possibility with the support of the NHLBI, the NIDDK, and the Alliance for Lupus Research.
2) We are also using genetic approaches to identify metabolic pathways that are essential for T cell activation and establishment of functional subsets. This work has focused on the glucose transporter Glut1 to date and we have now a panel of tools to directly modify T cell metabolism in vivo. We have found that Glut1 overexpression in T cells can augment T cell activation and is sufficient to lead to an inflammatory disorder as mice age that resembles Systemic Lupus Erythematosus. Glut1 is regulated by activation of the PI3K/Akt signaling pathway and ectopic activation of this pathway leads to a similar inflammatory phenotype. We are now using a variety of conditional gene knockout animal models and siRNA for metabolic genes in glycolysis, glutamine metabolism, and other pathways to test the role of these pathways in vivo in models of inflammatory disease and anti-tumor immunity. These studies are supported by the NIDDK.
3) The tumor microenvironment greatly alters the nutrients that are available for T cells and can greatly impact T cell metabolism and anti-tumor immunity. We are studying the metabolic profile of T cells in clear cell Renal Cell Carcinoma (ccRCC) patients and in animal models of T cell/tumor interactions. We aim to identify metabolic barriers for anti-tumor immunity and to determine how therapies that modulate anti-tumor immunity may impact T cell metabolism and function. These studies are supported by the Cancer Research Institute and the Forbeck Foundation.
4) The metabolic regulation of leukemic cell proliferation and survival is also a key area of investigation in the Rathmell lab. These studies focus on acute lymphoblastic leukemia (ALL) of both T cell and B cell origins. Our focus is to define how leukemic transformation alters lymphocyte metabolism and we have found several key differences specific to leukemia. By genetically targeting metabolic pathways in vivo we are now testing the metabolic adaptation and stress response of cancer cells to metabolic inhibition. These studies are supported by the NCI.
Our approach to study the mechanism and role of metabolic regulation in lymphocytes bridges immunology, cancer, and metabolism research. No cell can survive or properly function without the appropriate nutrietns and metabolic program. By examining the selective requirements for metabolic pathways in T cell subsets and leukemia we hope to identify new approaches to treat inflammatory diseases or cancer.