NK Cell Metabolism and TGFβ - Implications for Immunotherapy

Abstract

NK cells are innate lymphocytes which play an essential role in protection against cancer and viral infection. Their functions are dictated by many factors including the receptors they express, cytokines they respond to and changes in the external environment. These cell processes are regulated within NK cells at many levels including genetic, epigenetic and expression (RNA and protein) levels. The last decade has revealed cellular metabolism as another level of immune regulation. Specific immune cells adopt metabolic configurations that support their functions, and this is a dynamic process with cells undergoing metabolic reprogramming during the course of an immune response. Upon activation with pro-inflammatory cytokines, NK cells upregulate both glycolysis and oxphos metabolic pathways and this supports their anti-cancer functions. Perturbation of these pathways inhibits NK cell effector functions. Anti-inflammatory cytokines such as TGFβ can inhibit metabolic changes and reduce functional outputs. Although a lot remains to be learned, our knowledge of potential molecular mechanisms involved is growing quickly. This review will discuss our current knowledge on the role of TGFβ in regulating NK cell metabolism and will draw on a wider knowledge base regarding TGFβ regulation of cellular metabolic pathways, in order to highlight potential ways in which TGFβ might be targeted to contribute to the exciting progress that is being made in terms of adoptive NK cell therapies for cancer.

Keywords: NK cells; TGFβ; immunotherapy; metabolism; mitochondria.

Figure 1

Metabolism drives immune cell function. Glucose is metabolized by glycolysis, which is essential for activated NK cells, T cells, B cells, dendritic cells (DCs), M1 macrophages and granulocytes. Pyruvate can be converted to lactate and secreted from the cell or else it can be converted to acetyl CoA which feeds into the TCA cycle. The TCA cycle results in the production of reducing equivalents (NADH, FADH) which feed into the electron transport chain. The electron transport chain uses the electrons supplied by NADH and FADH to pump protons across the inner membrane. This force is then used to drive ATP synthase which makes ATP. Oxphos is important for immune cells when they are at rest, and it is also essential for activated NK cells, T cells, M2 macrophages and B cells. Acetyl CoA can alternatively be supplied by fatty acids—this form of metabolism is important for memory cells, regulatory cells and M2 macrophages. Glutamine can feed into the TCA cycle via glutaminolysis—this pathway is used by T cells and to a lesser extent, NK cells.

Figure 2

NK cell metabolism. Activated NK cells metabolize glucose to pyruvate. Pyruvate is converted to acetyl CoA which is then converted into citrate. Citrate is exported into the cytosol via SLC25A1, where it is converted into oxaloacetate and acetyl CoA. Acetyl CoA can then be used in acetylation reactions or for lipid synthesis. Oxaloacetate is converted back in malate, resulting in the production of NAD⁺, and essential cofactor for glycolysis. Malate is transported back into the mitochondria, where it is converted back into oxaloacetate, producing NADH which can then feed into the electron transport chain for ATP synthesis.

Figure 3

Potential roles for TGFβ in regulating NK cell metabolism. TGFβ has been shown to impact the metabolism of various non-immune cell types. This included reduced cMyc activity, reduced ER-mitochondrial signaling, increased ROS and reduced antioxidants, increased mitochondrial membrane potential and increased mitochondrial mass.

Figure 4

NK cell immunotherapy. Antibody therapy stimulates NK cell ADCC activity in vivo which promotes tumor killing. Autologous cell transfer therapy involves treating a patient's own NK cells, while allogeneic cell transfer therapy involves treating cells from a third party—healthy donor, cord blood, stem cells, or NK cell lines. These NK cells can be manipulated ex vivo pharmacologically or genetically such that they have enhanced anti-tumor functions and then infused into the patient. iPSC, induced pluripotent stem cells.