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

doi:10.1073/pnas.1113873109

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

Research output: Contribution to journal › Article › peer-review

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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 language	English
Pages (from-to)	2497-2502
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	109
Issue number	7
DOIs	https://doi.org/10.1073/pnas.1113873109
Publication status	Published - 14 Feb 2012

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PNAS 2012 finalFinal published version, 775 KB

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2 Finished

tryptophane 2,3-dioxygénase
WOUTERS, J.
1/10/11 → 30/09/13
Project: Research
Design, synthesis and study of enzyme modulators implicated in tryptophan metabolism and particularly in the kynurenin pathway
FREDERICK, R.
1/10/07 → 30/09/10
Project: Research

Physical Chemistry and characterization(PC2)
Johan Wouters (Manager) & Carmela Aprile (Manager)
Technological Platform Physical Chemistry and characterization
Facility/equipment: Technological Platform

5 Participation in conference

Heterocycles in Bio-organic Chemistry
Eduard Dolusic (Poster)
27 May 2013
Activity: Participating in or organising an event types › Participation in conference
BOSS XIII - 13th Belgian Organic Synthesis Symposium Louvain, 15 - 20 juillet 2012
Eduard Dolusic (Poster)
15 Jul 2012
Activity: Participating in or organising an event types › Participation in conference
Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (Medchem 2011)
Eduard Dolusic (Poster)
25 Nov 2011
Activity: Participating in or organising an event types › Participation in conference

USPJEH MLADOGA OGULINCA
Eduard Dolusic
24/02/12
1 item of Media coverage
Press/Media: Other
Mladi Ogulinac u ekipi koja je na tragu lijeka protiv raka
Eduard Dolusic
24/02/12
1 item of Media coverage
Press/Media: Other
Ogulinac Eduard Dolušić nadomak otkriću lijeka protiv raka
Eduard Dolusic
23/02/12
1 item of Media coverage
Press/Media: Other

Caractérisation enzymatique et structurale d'inhibiteurs indoliques de la tryptophane 2,3-dioxygénase.: Mémoire présenté pour l'obtention du grade académique de Master en Chimie "Chimie du Vivant et des Nanomatériaux" : Finalité Spécialisée.
Author: Molle, N., 2012
Supervisor: Wouters, J. (Supervisor), Dolusic, E. (Jury), Moineaux, L. (Jury), Fonder, G. (Jury) & Leherte, L. (Jury)
Student thesis: Master types › Master in Chemistry

Cite this

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. (2012). Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proceedings of the National Academy of Sciences of the United States of America, 109(7), 2497-2502. https://doi.org/10.1073/pnas.1113873109

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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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.",

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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, BJ 2012, 'Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 7, pp. 2497-2502. https://doi.org/10.1073/pnas.1113873109

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 journal › Article › peer-review

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AU - Dolušić, E.

AU - Frédérick, R.

AU - De Plaen, E.

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AU - Van Den Eynde, B.J.

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