Cited by 326Cancer Immunotherapy and BiomarkersTryptophan and brain disordersBacterial Cancer Therapy

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Reversal of indoleamine 2,3-dioxygenase-mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme

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Triplett, Todd A, Garrison, Kendra C, Marshall, Nicholas, Donkor, Moses, Blazeck, John, Lamb, Candice, Qerqez, Ahlam, Dekker, Joseph D, Tanno, Yuri, Lu, Wei-Cheng, Karamitros, Christos S, Ford, Kyle, Tan, Bing, Zhang, Xiaoyan M, McGovern, Karen, Coma, Silvia, Kumada, Yoichi, Yamany, Mena S, Sentandreu, Enrique, Fromm, George, Tiziani, Stefano, Schreiber, Taylor H, Manfredi, Mark, Ehrlich, Lauren I R, Stone, Everett, Georgiou, George·2018·Nature Biotechnology

DOI 10.1038/nbt.4180PMC PMC6078800

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Abstract

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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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
Publisher: Springer Science and Business Media LLC
Published: 2018-07-16
Volume: 36
Issue: 8
Pages: 758-764
ISSN: 0733-222X (ISSN-L)
1087-0156
1546-1696
DOI: 10.1038/nbt.4180
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: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
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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Reversal of indoleamine 2,3-dioxygenase-mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme

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