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

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Résumé

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.

langue originale	Anglais
Pages (de - à)	2497-2502
Nombre de pages	6
journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	109
Numéro de publication	7
Les DOIs	https://doi.org/10.1073/pnas.1113873109
Etat de la publication	Publié - 14 févr. 2012

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10.1073/pnas.1113873109

PNAS 2012 finalVersion finale publiée, 775 KB

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497 Citations
11 Poster
3 Revue de documentation
3 Article
1 Article dans les actes d'une conférence/un colloque

3-ALKENYL INDOLES AS TRYPTOPHAN 2,3-DIOXYGENASE INHIBITORS FOR THE ENHANCEMENT OF CANCER IMMUNOTHERAPY
Dolušić, E., Pilotte, L., Moineaux, L., Larrieu, P., Stroobant, V., Colau, D., Pochet, L., De Plaen, E., Uyttenhove, C., Van den Eynde, B., Wouters, J., Masereel, B., Lanners, S. & Frédérick, R., 27 mai 2013, p. Book of Abstracts, Heterocycles in Bio-organic Chemistry, Riga, Latvia, 27 - 30 May 2013, PO129. 1 p.
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Reversal of Tumoral Immune Resistance by Inhibition of Tryptophan 2,3-Dioxygenase (TDO): Design, Synthesis and Preclinical Evaluation of a Novel TDO Inhibitor.
Dolušić, E., Larrieu, P., Moineaux, L., Stroobant, V., Pilotte, L., Colaux, D., Van den Eynde, B., Masereel, B., Wouters, J. & Frédérick, R., 2012, Dans: ChemMedChem. p. 371 1 p.
Résultats de recherche: Contribution à un journal/une revue › Revue de documentation › Revue par des pairs
Synthesis, crystal structures and electronic properties of isomers of chloro-pyridinylvinyl-1H-indoles
Moineaux, L., Laurent, S., Reniers, J., Dolusic, E., Galleni, M., Frère, J-M., Masereel, B., Frédérick, R. & Wouters, J., 1 août 2012, Dans: European Journal of Medicinal Chemistry. 54, p. 95-102 8 p.
Résultats de recherche: Contribution à un journal/une revue › Article › Revue par des pairs

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2 Terminé

tryptophane 2,3-dioxygénase
Wouters, J.
1/10/11 → 30/09/13
Projet: Recherche
Conception, synthèse et étude de modulateurs d'enzymes impliquées dans le métabolisme du tryptophane, et en particulier dans la voie de la kynurénine.
FREDERICK, R.
1/10/07 → 30/09/10
Projet: Recherche

Physico-chimie et caractérisation (PC2)
Johan Wouters (!!Manager) & Carmela Aprile (!!Manager)
Plateforme technologique Caracterisation physico-chimiques
Equipement/installations: Plateforme technolgique

5 Participation à une conférence, un congrès

Heterocycles in Bio-organic Chemistry
Eduard Dolusic (Poster)
27 mai 2013
Activité: Participation ou organisation d'un événement › Participation à une conférence, un congrès
BOSS XIII - 13th Belgian Organic Synthesis Symposium Louvain, 15 - 20 juillet 2012
Eduard Dolusic (Poster)
15 juil. 2012
Activité: Participation ou organisation d'un événement › Participation à une conférence, un congrès
Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (Medchem 2011)
Eduard Dolusic (Poster)
25 nov. 2011
Activité: Participation ou organisation d'un événement › Participation à une conférence, un congrès

Mladi Ogulinac u ekipi koja je na tragu lijeka protiv raka
Eduard Dolusic
24/02/12
1 élément de Couverture média
Presse/Médias: Autre
USPJEH MLADOGA OGULINCA
Eduard Dolusic
24/02/12
1 élément de Couverture média
Presse/Médias: Autre
Ogulinac Eduard Dolušić nadomak otkriću lijeka protiv raka
Eduard Dolusic
23/02/12
1 élément de Couverture média
Presse/Médias: Autre

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.
Auteur: Molle, N., 2012
Superviseur: Wouters, J. (Promoteur), Dolusic, E. (Jury), Moineaux, L. (Jury), Fonder, G. (Jury) & Leherte, L. (Jury)
Student thesis: Master types › Master en sciences chimiques

Contient cette citation

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

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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, Numéro 7, p. 2497-2502. https://doi.org/10.1073/pnas.1113873109

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AU - Pilotte, L.

AU - Larrieu, P.

AU - Stroobant, V.

AU - Colau, D.

AU - Dolušić, E.

AU - Frédérick, R.

AU - De Plaen, E.

AU - Uyttenhove, C.

AU - Wouters, J.

AU - Masereel, B.

AU - Van Den Eynde, B.J.

PY - 2012/2/14

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N2 - 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.

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

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