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Reversal of indoleamine 2,3-dioxygenase-mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme
Open accessAbstract
Increased tryptophan (Trp) catabolism in the tumor microenvironment (TME) can mediate immune suppression by upregulation of interferon (IFN)-γ-inducible indoleamine 2,3-dioxygenase (IDO1) and/or ectopic expression of the predominantly liver-restricted enzyme tryptophan 2,3-dioxygenase (TDO). Whether these effects are due to Trp depletion in the TME or mediated by the accumulation of the IDO1 and/or TDO (hereafter referred to as IDO1/TDO) product kynurenine (Kyn) remains controversial. Here we show that administration of a pharmacologically optimized enzyme (PEGylated kynureninase; hereafter referred to as PEG-KYNase) that degrades Kyn into immunologically inert, nontoxic and readily cleared metabolites inhibits tumor growth. Enzyme treatment was associated with a marked increase in the tumor infiltration and proliferation of polyfunctional CD8+ lymphocytes. We show that PEG-KYNase administration had substantial therapeutic effects when combined with approved checkpoint inhibitors or with a cancer vaccine for the treatment of large B16-F10 melanoma, 4T1 breast carcinoma or CT26 colon carcinoma tumors. PEG-KYNase mediated prolonged depletion of Kyn in the TME and reversed the modulatory effects of IDO1/TDO upregulation in the TME.
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“Synergistic activity with anti-PD1 has also been demonstrated (73,74).”
From Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan–Kynurenine–Aryl Hydrocarbon Axis (2019) · cites this paper as [73]
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“Novel Trp-Kyn-AhR inhibitors have demonstrated promising pre-clinical activity”
From Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan–Kynurenine–Aryl Hydrocarbon Axis (2019) · cites this paper as [73]
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Metadata
- Authors
- Triplett, T. A., Garrison, K. C., Marshall, N., Donkor, M., Blazeck, J., Lamb, C., Qerqez, A., Dekker, J. D., Tanno, Y., Lu, W.-C., Karamitros, C. S., Ford, K., Tan, B., Zhang, X. M., McGovern, K., Coma, S., Kumada, Y., Yamany, M. S., Sentandreu, E., Fromm, G., Tiziani, S., Schreiber, T. H., Manfredi, M., Ehrlich, L. I. R., Stone, E., & Georgiou, G.
- Affiliations
- The University of Texas at Austin (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Kyoto Institute of Technology (JP)
- Heat Biologics (United States) (US)
- Corresponding author
- Stone, Everett
- Georgiou, George
- ORCID
- Triplett, Todd A
- Marshall, Nicholas
- Blazeck, John
- Lamb, Candice
- Qerqez, Ahlam
- Dekker, Joseph D
- Tanno, Yuri
- Karamitros, Christos S
- Ford, Kyle
- Tan, Bing
- Zhang, Xiaoyan M
- McGovern, Karen
- Kumada, Yoichi
- Sentandreu, Enrique
- Fromm, George
- Tiziani, Stefano
- Schreiber, Taylor H
- Manfredi, Mark
- Ehrlich, Lauren I R
- Stone, Everett
- Georgiou, George
- Venue
- Nature Biotechnology
- Published
- 2018-07-16
- Volume
- 36
- Issue
- 8
- Pages
- 758-764
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC6078800
- OpenAlex
- W2883967352
- Cited by
- 321
- References
- 40
- Citations by year
- 2026: 39 · 2025: 40 · 2024: 52 · 2023: 43 · 2022: 49 · 2021: 44 · 2020: 29 · 2019: 22 · 2018: 3
- FWCI
- 9.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA189623)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Bacterial Cancer Therapy
- Keywords
- indoleamine 2,3-dioxygenase, tryptophan 2,3-dioxygenase, kynurenine, kynureninase, tumor immunosuppression, tryptophan catabolism, tumor microenvironment, CD8+ T cells, immune checkpoint inhibitors, cancer vaccines, melanoma, breast cancer, colon cancer, enzyme therapy
- MeSH terms
- Adjuvants, Immunologic, Animals, Humans, Hydrolases, Kynurenine, Neoplasms, Cancer Vaccines, Cell Line, Tumor, Indoleamine-Pyrrole 2,3,-Dioxygenase, Tumor Microenvironment
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