When Cells Suffocate: Autophagy in Cancer and Immune Cells under Low Oxygen

Figure 3

Signalling events and metabolic consequences in T cells. In the absence of activation signals, naïve cells utilize oxidative phosphorylation (OxPhos) as the main source of cellular bioenergetics. This is in part supported by basal levels of autophagy necessary to maintain energy and protein turnover homeostasis. Within the first hour of T cell activation, AMPK activity predominates leading to suppression of mTOR which results in upregulation of glycolysis, OxPhos as well as autophagy. Together these pathways provide the initial wave of bioenergetics to support growth. During the transition to the proliferative state, AMPK signalling declines and mTOR activity increases which in turn enforces nutrient uptake and glycolysis. As effector T cells enter the hypoxic tumor microenvironment, HIF-1α accumulation reduces OxPhos and further augments glucose-dependent metabolism. At later stages of prolonged hypoxia, exhaustion of glucose activates AMPK leading to mTOR suppression and the activation of autophagy-dependent survival and effector T cell antitumor function.