The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy

Abstract

Breakthroughs in anti-tumor immunity have led to unprecedented advances in immunotherapy, yet it is now clear that the tumor microenvironment (TME) restrains immunity. T cells must substantially increase nutrient uptake to mount a proper immune response and failure to obtain sufficient nutrients or engage the appropriate metabolic pathways can alter or prevent effector T cell differentiation and function. The TME, however, can be metabolically hostile due to insufficient vascular exchange and cancer cell metabolism that leads to hypoxia, depletion of nutrients, and accumulation of waste products. Further, inhibitory receptors present in the TME can inhibit T cell metabolism and alter T cell signaling both directly and through release of extracellular vesicles such as exosomes. This review will discuss the metabolic changes that drive T cells into different stages of their development and how the TME imposes barriers to the metabolism and activity of tumor infiltrating lymphocytes.

Keywords: cancer; cancer biology; immunology; immunometabolism; immunotherapy; inflammation; t cells; tumor microenvironment; tumor-infiltrating lymphocytes.

Figure 1.. T Cells Undergo Metabolic Rewiring in Different Stages of Their Life.

(A) Naïve T cells uptake sufficient amounts of glucose to fuel oxidative phosphorylation and survive as they survey antigens. (B) Upon encountering cognate antigen, activated T cells rapidly uptake glucose and glutamine to fuel their bioenergetic needs. Activated T cells perform aerobic glycolysis, which shunts products of glycolysis to biosynthetic processes necessary for proliferation and effector function and generates lactate as a byproduct. (C) Once the antigen is cleared, T cells can form long-lived memory cells in which AMPK signaling stimulates fatty acid oxidation. Memory T cells also increase their mitochondrial mass and spare respiratory capacity to prepare for future encounter with cognate antigen. (D) T cells can become exhausted if they fail to clear antigens such as during chronic infections or cancer. T lymphocytes isolated from tumors display elevated levels of PD-1, which decreases PI3K/Akt/mTOR signaling and glycolysis. Exhausted TILs rely on fatty acid oxidation, though they often have dysfunctional mitochondria and decreased mitochondrial mass as well.