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Proc Natl Acad Sci U S A. 2012 Feb 14;109(7):2497-502. doi: 10.1073/pnas.1113873109. Epub 2012 Jan 30.

Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase.

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1
Ludwig Institute for Cancer Research, Brussels Branch, and de Duve Institute, Université Catholique de Louvain, B-1200 Brussels, Belgium.

Abstract

Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO1) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance, and IDO1 inhibition is an active area of drug development. Tryptophan 2,3-dioxygenase (TDO) is an unrelated hepatic enzyme that also degrades tryptophan along the kynurenine pathway. Here, we show that enzymatically active TDO is expressed in a significant proportion of human tumors. In a preclinical model, TDO expression by tumors prevented their rejection by immunized mice. We developed a TDO inhibitor, which, upon systemic treatment, restored the ability of mice to reject TDO-expressing tumors. Our results describe a mechanism of tumoral immune resistance based on TDO expression and establish proof-of-concept for the use of TDO inhibitors in cancer therapy.

PMID:
22308364
PMCID:
PMC3289319
DOI:
10.1073/pnas.1113873109
[Indexed for MEDLINE]
Free PMC Article
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