Indoleamine 2,3-Dioxygenase: Is It an Immune Suppressor? : The Cancer Journal (original) (raw)

Special Issue on Immunotherapy of Cancer: Review Article

Is It an Immune Suppressor?

Soliman, Hatem MD; Mediavilla-Varela, Melanie PhD; Antonia, Scott MD, PhD

From the Women's Oncology Department; Antonia Lab Department of Immunology; and Moffitt Cancer Center and Research Institute, Tampa, FL.

Reprints: Hatem Soliman, MD, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612. E-mail: [email protected].

Abstract

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 IFNγ 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.