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

L. Pilotte, P. Larrieu, V. Stroobant, D. Colau, E. Dolušić, R. Frédérick, E. De Plaen, C. Uyttenhove, J. Wouters, B. Masereel, B.J. Van Den Eynde

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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.
Original languageEnglish
Pages (from-to)2497-2502
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number7
DOIs
Publication statusPublished - 14 Feb 2012

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Tryptophan Oxygenase
Tryptophan
Neoplasms
Indoleamine-Pyrrole 2,3,-Dioxygenase
Peripheral Tolerance
Kynurenine
Immune Tolerance
Liver
Enzymes
Therapeutics

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Pilotte, L. ; Larrieu, P. ; Stroobant, V. ; Colau, D. ; Dolušić, E. ; Frédérick, R. ; De Plaen, E. ; Uyttenhove, C. ; Wouters, J. ; Masereel, B. ; Van Den Eynde, B.J. / Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 7. pp. 2497-2502.
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Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. / Pilotte, L.; Larrieu, P.; Stroobant, V.; Colau, D.; Dolušić, E.; Frédérick, R.; De Plaen, E.; Uyttenhove, C.; Wouters, J.; Masereel, B.; Van Den Eynde, B.J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 7, 14.02.2012, p. 2497-2502.

Research output: Contribution to journalArticle

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AU - Colau, D.

AU - Dolušić, E.

AU - Frédérick, R.

AU - De Plaen, E.

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AU - Van Den Eynde, B.J.

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