The metabolism of the
essential amino acid tryptophan is a key microenvironmental factor shaping the immunobiology of many
tumor types. The current concept suggests that in the tumor microenvironment,
tryptophan is metabolized by specialized
dioxygenases, chiefly indoleamine-2,3-dioxygenase (IDO), which is expressed by
tumor cells and antigen-presenting cells. High IDO activity leads to the depletion of
tryptophan from the local microenvironment, while immediate
tryptophan metabolites, particularly
kynurenine, accumulate to high micromolar levels. Both the depletion of
tryptophan and the accumulation of
kynurenine lead to profound suppression of T-cell responses. Orally active IDO inhibitors are currently being explored in clinical trials for their efficacy in enhancing antitumor immune responses. Recent evidence points at alternative routes of
tryptophan catabolism via tryptophan-2,3-dioxygenase, which is particularly expressed in
malignant gliomas resulting in the production of high amounts of
kynurenine. Tryptophan-2,3-dioxygenase-derived
kynurenine in turn leads to the promotion of
glioma growth and invasiveness and the suppression of antitumor immune responses by binding to the
aryl hydrocarbon receptor expressed in
glioma cells and
glioma-infiltrating T cells. These new data open up novel therapeutic approaches to alleviate
glioma-mediated immunosuppression. This review summarizes the current view on the relevance of
tryptophan metabolism as an important immunosuppressive, proinvasive and growth-promoting metabolic pathway in
malignant glioma.