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IDO1 in cancer: a Gemini of immune checkpoints

Cellular & Molecular Immunology volume 15, pages 447–457 (2018)Cite this article

Abstract

Indoleamine 2, 3-dioxygenase 1 (IDO1) is a rate-limiting metabolic enzyme that converts the essential amino acid tryptophan (Trp) into downstream catabolites known as kynurenines. Coincidently, numerous studies have demonstrated that IDO1 is highly expressed in multiple types of human cancer. Preclinical studies have further introduced an interesting paradox: while single-agent treatment with IDO1 enzyme inhibitor has a negligible effect on decreasing the established cancer burden, approaches combining select therapies with IDO1 blockade tend to yield a synergistic benefit against tumor growth and/or animal subject survival. Given the high expression of IDO1 among multiple cancer types along with the lack of monotherapeutic efficacy, these data suggest that there is a more complex mechanism of action than previously appreciated. Similar to the dual faces of the astrological Gemini, we highlight the multiple roles of IDO1 and review its canonical association with IDO1-dependent tryptophan metabolism, as well as documented evidence confirming the dispensability of enzyme activity for its immunosuppressive effects. The gene transcript levels for IDO1 highlight its strong association with T-cell infiltration, but the lack of a universal prognostic significance among all cancer subtypes. Finally, ongoing clinical trials are discussed with consideration of IDO1-targeting strategies that enhance the efficacy of immunotherapy for cancer patients.

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Acknowledgements

This work was supported by NIH grants R00 NS082381 (DAW) and R01 NS097851-01 (DAW), the Cancer Research Institute—Clinic and Laboratory Integration Program (DAW), the Robert H. Lurie Comprehensive Cancer Center—Zell Scholar Program of the Zell Family Foundation Gift (DAW) and the Northwestern Brain Tumor Institute.

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Authors and Affiliations

  1. Department of Neurological Surgery, Northwestern University, Chicago, USA

    Lijie Zhai, Erik Ladomersky, Brenda Nguyen, Ricky Patel, Kristen L Lauing, Meijing Wu & Derek A Wainwright

  2. Department of Pediatrics, Northwestern University, Chicago, USA

    Alicia Lenzen

  3. Division of Hematology, Oncology and Stem Cell Transplantation, Northwestern University, Chicago, USA

    Alicia Lenzen

  4. Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University, Chicago, USA

    Alicia Lenzen

  5. Department of Medicine-Hematology/Oncology, Northwestern University, Chicago, USA

    Derek A Wainwright

  6. Department of Microbiology-Immunology, Northwestern University, Chicago, USA

    Derek A Wainwright

  7. Department of Medicine-Division of Hematology and Oncology, Northwestern University; Brain Tumor Institute, Northwestern University, Chicago, USA

    Derek A Wainwright

  8. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Northwestern University, 60611, Chicago, IL, USA

    Derek A Wainwright

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  1. Lijie Zhai
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Zhai, L., Ladomersky, E., Lenzen, A. et al. IDO1 in cancer: a Gemini of immune checkpoints. Cell Mol Immunol 15, 447–457 (2018). https://doi.org/10.1038/cmi.2017.143

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