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The role of IDO in brain tumor immunotherapy

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Abstract

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.

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Acknowledgments

This work was supported by an American Brain Tumor Association Discovery Grant (D.A.W.), as well as NIH grants NIH F32 NS073366 (D.A.W.), NIH K99 NS082381 (D.A.W.), NIH R00 NS082381 (D.A.W.) R01 CA138587 (M.S.L.), NIH R01 CA122930 (M.S.L.), NIH U01 NS069997 (M.S.L.).

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The authors declare that no competing interests exist.

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Authors and Affiliations

  1. Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, 300 East Superior Street, Tarry Building 2-703, Chicago, IL, 60611, USA

    Lijie Zhai, Kristen L. Lauing, Jun Qian & Derek A. Wainwright

  2. The Brain Tumor Center, The University of Chicago Pritzker School of Medicine, Chicago, IL, 60637, USA

    Alan L. Chang, Mahua Dey & Maciej S. Lesniak

  3. Shanghai East Hospital, The Institute for Biomedical Engineering and Nano Science, Tongji University School of Medicine, Shanghai, China

    Yu Cheng

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  1. Lijie Zhai
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  2. Kristen L. Lauing
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  5. Jun Qian
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  8. Derek A. Wainwright
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Correspondence to Derek A. Wainwright.

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Zhai, L., Lauing, K.L., Chang, A.L. et al. The role of IDO in brain tumor immunotherapy. J Neurooncol 123, 395–403 (2015). https://doi.org/10.1007/s11060-014-1687-8

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