Metabolic Checkpoints: Novel Avenues for Immunotherapy of Cancer

Abstract

Novel therapies targeting immune checkpoint molecules have redefined the treatment of cancer at advanced stages and brought hope to millions of patients worldwide. Monoclonal antibodies targeting immune-inhibitory receptors often lead to complete and objective responses as well as to durable progression-free survival where all other therapeutic approaches fail. Yet, many tumors show significant resistance to checkpoint blockade through mechanisms that are only starting to come to light. An alluring alternative strategy to reinvigorate anticancer immune responses comes from the emerging field of immuno-metabolism. Over the past few years, numerous studies revealed that many well-known metabolic playmakers also serve as critical checkpoints in immune homeostasis and immunity against tumors. Here, we survey recent insights into the intimate and intertwining links between T cell metabolic programs and environmental cues in the tumor milieu. Transferring these new findings from the bench to the bedside may soon entirely re-shape the field of cancer immunotherapy and significantly improve the lives of patients.

Keywords: PD-1; cancer immunotherapy; checkpoint blockade; immune checkpoints; mammalian target of rapamycin pathway; metabolic checkpoints.

Figure 1

Rapidly proliferating tumor cells avidly consume nutrients from the microenvironment, thereby outcompeting T cells in a contest for metabolic fitness. Increased activity of hypoxia-inducible factor-1α (HIF-1α) driven by tumor hypoxia further intensifies glycolysis and exacerbates the paucity of glucose in the milieu. This results in T cell deprivation of essential fuel for their effector function, resulting in a thwarted antitumor immune response. PD-1 signaling in T cells dampens their glycolytic activity and proliferation, while PD-1 ligand (PD-L1) ligation leads to opposite effects in cancer cells.