Indoleamine 2,3-Dioxygenase

This article covers what is currently known about the role of the enzyme indoleamine 2,3-dioxygenase (IDO) in cancer-related immunosuppression and the clinical research on IDO inhibitors. A PUBMED search was performed using the terms IDO, indoleamine 2,3-dioxygenase, 1-MT. IDO is an inducible enzyme that catalyzes the rate-limiting first step in tryptophan catabolism. This enzyme is overexpressed in response to IFNgamma in a variety of different malignancies. IDO causes immunosuppression through breakdown of tryptophan in the tumor microenvironment and tumor-draining lymph nodes. The depletion of tryptophan and toxic catabolites renders effector T cells inactive and dendritic cells immunosuppressive. Preclinical data suggest that IDO inhibition can delay tumor growth, enhance dendritic cell vaccines, and synergize with chemotherapy through immune-mediated mechanisms. The lead IDO inhibitor, d-1-methyl-tryptophan (d-1-MT), was selected for phase I trials and seems to have immune modulating activity. Subsequently, another isoform of IDO, IDO2, was discovered and found to be the target of d-1-MT. Multiple single-nucleotide polymorphisms in IDO2 affecting its catalytic activity may serve as a pharmacogenetic predictive biomarker for d-1-MT. The IDO pathway is an important mechanism of tumor-related immunosuppression and blocking it could improve cancer immunotherapy outcomes. Clinical development of d-1-MT and other IDO inhibitors as systemic immunomodulators to be combined with other immune modulators, vaccines, and chemotherapy are ongoing.