Tumor immune escape mediated by indoleamine 2,3-dioxygenase

Abstract

Amongst the numerous mediators contributing towards the escape of tumors from the host's immune response against them, the enzyme indoleamine 2,3-dioxygenase (IDO) has recently attracted special attention. By catabolizing tryptophan to N-formyl-kynurenine, IDO starves T cells from this important amino acid rendering them incapable of mounting appropriate immune responses. Originally, IDO has been associated to peripheral tolerance and maternal tolerance towards the fetus. The recent identification of IDO-expressing tumor cells has implicated this molecule as a key mediator of the tumor immune escape. Mounting evidence indicates that, within the tumor microenvironment, not only tumor cells but also other infiltrating cells such as dendritic cells, monocytes and others can be sources of IDO. IDO-induced tryptophan depletion from the tumor microenvironment could be the result of either elevated levels of the enzyme or augmented tryptophan consumption by both tumor cells and antigen presenting cells of the host. Beyond the tryptophan depletion, accumulation of its metabolites into the tumor environment seems to also propagate the suppression of anti-tumor immune responses. Finally, evidence emerges indicating that IDO possibly promotes tumor immune escape by inducing an immunoregulatory or an anergic T cell phenotype at a systemic level. In this context, anti-IDO therapeutic approaches are already under investigation, considering 1-methyl-tryptophan, its analogues as well as newly identified chemicals and natural extracts.