Partners in crime: The feedback loop between metabolic reprogramming and immune checkpoints in the tumor microenvironment

Abstract

The tumor microenvironment (TME) is a complex and constantly changing cellular system composed of heterogeneous populations of tumor cells and non-transformed stromal cells, such as stem cells, fibroblasts, endothelial cells, pericytes, adipocytes, and innate and adaptive immune cells. Tumor, stromal, and immune cells consume available nutrients to sustain their proliferation and effector functions and, as a result of their metabolism, produce a wide array of by-products that gradually alter the composition of the milieu. The resulting depletion of essential nutrients and enrichment of by-products work together with other features of the hostile TME to inhibit the antitumor functions of immune cells and skew their phenotype to promote tumor progression. This review briefly describes the participation of the innate and adaptive immune cells in recognizing and eliminating tumor cells and how the gradual metabolic changes in the TME alter their antitumor functions. In addition, we discuss the overexpression of the immune checkpoints and their ligands as a result of nutrient deprivation and by-products accumulation, as well as the amplification of the metabolic alterations induced by the immune checkpoints, which creates an immunosuppressive feedback loop in the TME. Finally, the combination of metabolic and immune checkpoint inhibitors as a potential strategy to treat cancer and enhance the outcome of patients is highlighted.

Glutaminolysis of CD4+ T Cells: A Potential Therapeutic Target in Viral Diseases

“…CD4 + T cells participate in antiviral immunity mainly through the production of the cytokines IFN-γ and TNF and direct cytolytic effects. 71 , 72 On the one hand, competition for glutamine exists between immune cells and host cells, 73 and postinfection viral manipulation of host cells increases glutaminolysis, forcing immune cells to switch to noneffector cells ( Figure 2 ); at the same time, sustained activation of CD4 + T cell checkpoint/suppressor receptor expression leads to effector cell exhaustion, weakening the immune response. On the other hand, uncontrolled immune cell homeostasis within the microenvironment after viral infection produces cytokine storms that adversely affect the organism.…”