The role of IDO in brain tumor immunotherapy

Malignant glioma comprises the majority of primary brain tumors. Coincidently, most of those malignancies express an inducible tryptophan catabolic enzyme, indoleamine 2,3 dioxygenase 1 (IDO1). While IDO1 is not normally expressed at appreciable levels in the adult central nervous system, it’s rapid...

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Bibliographic Details
Published in:Journal of neuro-oncology 2015-07, Vol.123 (3), p.395-403
Main Authors: Zhai, Lijie, Lauing, Kristen L., Chang, Alan L., Dey, Mahua, Qian, Jun, Cheng, Yu, Lesniak, Maciej S., Wainwright, Derek A.
Format: Article
Language:English
Subjects:
Animals
Brain Neoplasms - immunology
Brain Neoplasms - metabolism
Brain Neoplasms - therapy
Editors' Invited Manuscript
Humans
Immunotherapy - methods
Indoleamine-Pyrrole 2,3,-Dioxygenase - immunology
Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism
Medicine
Medicine & Public Health
Neurology
Oncology
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Summary:Malignant glioma comprises the majority of primary brain tumors. Coincidently, most of those malignancies express an inducible tryptophan catabolic enzyme, indoleamine 2,3 dioxygenase 1 (IDO1). While IDO1 is not normally expressed at appreciable levels in the adult central nervous system, it’s rapidly induced and/or upregulated upon inflammatory stimulus. The primary function of IDO1 is associated with conversion of the essential amino acid, tryptophan, into downstream catabolites known as kynurenines. The depletion of tryptophan and/or accumulation of kynurenine has been shown to induce T cell deactivation, apoptosis and/or the induction of immunosuppressive programming via the expression of FoxP3. This understanding has informed immunotherapeutic design for the strategic development of targeted molecular therapeutics that inhibit IDO1 activity. Here, we review the current knowledge of IDO1 in brain tumors, pre-clinical studies targeting this enzymatic pathway, alternative tryptophan catabolic mediators that compensate for IDO1 loss and/or inhibition, as well as proposed clinical strategies and questions that are critical to address for increasing future immunotherapeutic effectiveness in patients with incurable brain cancer.
ISSN:0167-594X
1573-7373
DOI:10.1007/s11060-014-1687-8