The DOI matches its Crossref record; 40 of the 40 references it cites were found in a registry or an index.
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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Cites
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An Interaction between Kynurenine and the Aryl Hydrocarbon Receptor Can Generate Regulatory T Cells
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Self-citationKynurenines: Tryptophan’s metabolites in exercise, inflammation, and mental health
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Indoleamine 2,3-dioxygenase and tumor-induced tolerance
Munn, D. H., & Mellor, A. L. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31178 · Cited by 1,093
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In Situ Cytotoxic and Memory T Cells Predict Outcome in Patients With Early-Stage Colorectal Cancer
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Tryptophan Catabolism in Cancer: Beyond IDO and Tryptophan Depletion
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Rothhammer, V., & Quintana, F. J. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-019-0125-8 · Cited by 1,197
Tryptophan metabolism in health and disease
Chen, X., Li, G., Zheng, Q., Gu, X., Shi, Q., Su, Y., Chu, Q., Yuan, X., Bao, Z., Lu, J., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.06.004 · Cited by 1,035
Therapy-Induced Evolution of Human Lung Cancer Revealed by Single-Cell RNA Sequencing
Maynard, A., McCoach, C. E., Rotow, J. K., Harris, L., Haderk, F., Kerr, D. L., Yu, E. A., Schenk, E. L., Tan, W., Zee, A., et al. (2020) · Cell · doi:10.1016/j.cell.2020.07.017 · Cited by 719
Tang, T., Huang, X., Zhang, G., Hong, Z., Bai, X., & Liang, T. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00449-4 · Cited by 618
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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