Fig. 2.

Metabolic enzymes and metabolites in immunosuppression. a Immunosuppression by metabolism of the amino acids tryptophan (upper part) or arginine (lower part). Tumor cells can express the enzymes indoleamine-2,3-dioxygenase (IDO), indoleamine-2,3-dioxygenase-like protein (IDO2), and tryptophan 2,3-dioxygenase (TDO). All these enzymes are able to catalyze the first step in kynurenine pathway of tryptophan metabolism. In addition, plasmacytoid DCs in the draining lymph nodes of cancer patients can express IDO and IDO2. The general depletion of tryptophan impairs T cell proliferation. Furthermore, immune modulatory tryptophan metabolites can induce apoptosis and affect activity of T and NK cells. IDO expressing plasmacytoid DCs can also trigger regulatory T cell (Treg) differentiation. Similarly, arginine depletion by arginase I (ARG1) or inducible nitric oxide synthase (iNOS) impairs T cell activation. iNOS can further suppress immune responses by recruitment and activation of MDSC. NO can be further converted into reactive oxygen species (ROS) and reactive nitrogen and oxygen species (RNOS). The latter can impair T cell migration into the tumor by nitrotyrosinylation of the chemokine CCL2. b Tumor cells primarily rely on glycolysis. One important enzyme involved is LDH converting pyruvate into lactate. Its expression is up-regulated by hypoxia or oncogenes. Lactate is secreted from the cells via monocarboxylate transporters accompanied by H⁺ transport decreasing the extracellular pH. Lactate affects many different processes like inhibition of cytotoxic T cell responses, causing chronic inflammation via triggering enhanced IL-17A cytokine secretion, or increasing secretion of angiogenic factors by endothelial cells (EC). c Immune suppression by adenosine (Ado). Extracellular ATP is converted by CD39 into ADP and then into AMP. CD73 converts AMP into Ado. Ado can be exported and imported from the tumor cell. HIF-1α enhances CD73 expression. Ado interaction with adenosine A2A receptor (A2AR) on T cells impairs their activity, whereas the binding to adenosine A2B receptor (A2BR) on MDSC promotes their recruitment and function. In addition, Ado inhibits the differentiation of Th17 cells, the activity of NK cells, and the maturation of DCs