Dysfunctional T cell metabolism in the tumor microenvironment

Abstract

Metabolic and signaling pathways are integrated to determine T cell fate and function. As stimulated T cells gain distinct effector functions, specific metabolic programs and demands are also adopted. These changes are essential for T cell effector function, and alterations or dysregulation of metabolic pathways can modulate T cell function. One physiological setting that impacts T cell metabolism is the tumor microenvironment. The metabolism of cancer cells themselves can limit nutrients and accumulate waste products. In addition to the expression of inhibitory ligands that directly modify T cell physiology, T cell metabolism may be strongly inhibited in the tumor microenvironment. This suppression of T cell metabolism may inhibit effector T cell activity while promoting suppressive regulatory T cells, and act as a barrier to effective immunotherapies. A thorough understanding of the effect of the tumor microenvironment on the immune system will support the continued improvement of immune based therapies for cancer patients.

Keywords: Glycolysis; Immunotherapy; Mitochondria; Oxidative phosphorylation; T-cell.

Fig.1

The metabolic programs of T cell subsets. Distinct T cell subsets utilize specific metabolic programs to support their functions. Each functional subset is characterized by signaling pathways, transcription factors, metabolic programs, and effector cytokines.

Fig. 2

Tumor cells inhibit effector T cell metabolism and function through multiple means. Tumor cells express CD39 and CD73 that can produce adenosine from extracellular ATP and IDO1 that can both deplete tryptophan and produce kynurenine. The metabolism of tumor cells also consumes glucose and can lead to lactate accumulation, both of which can suppress effector T cells and promote Treg. PD-1 can also influence T cell metabolism to suppress glycolysis and promote oxidative metabolism.