Evidence accumulating over the past decade indicates that activation of the tryptophan-degrading enzyme indoleamine-2,3-dioxygenase (IDO) represents a key pathway suppressing anti-cancer immunity. IDO is constitutively expressed by many tumors and creates an immunosuppressive microenvironment both by depletion of the essential amino acid tryptophan and by formation of immunosuppressive tryptophan metabolites such as kynurenine. IDO expression correlates with poor prognosis in patients with ovarian cancer, colorectal cancer and hematological malignancies such as B-cell lymphoma. In human cancers high expression of IDO is associated with reduced effector T-lymphocyte infiltration and increased number of regulatory T cells (Treg). Pharmacological inhibition of IDO restores anti-tumor immunity and suppresses tumor growth in preclinical models and is currently tested in clinical trials in cancer patients. Preclinical models using IDO-deficient mice indicate a key role for IDO in the regulation of carcinogenesis driven by chronic inflammation and in metastasis. While in preclinical models the induction and expression of IDO is controlled by tumor suppressor genes such as Bin-1 and oncogenes such as c-kit, respectively, the molecular mechanisms that drive constitutive IDO expression in human tumors are incompletely understood.
Litzenburger UM, Opitz CA, Sahm F, et al. Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR. Oncotarget. 2014;5(4):1038-1051