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

Résultats de recherche: Contribution à un journal/une revue › Article › Revue par des pairs

98 Téléchargements (Pure)

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

SDG des Nations Unies

Ce résultat contribue à ou aux Objectifs de développement durable suivants

Accès au document

10.1073/pnas.1113873109

PNAS 2012 finalVersion finale publiée, 775 KB

Autres fichiers et liens

Link to publication in Scopus

527 Citations
11 Poster
3 Revue de documentation
2 Article
1 Article dans les actes d'une conférence/un colloque
Afficher plus d’informations
- 1 Papier

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.
Résultats de recherche: Contribution à un événement scientifique (non publié) › Poster › Revue par des pairs

Accès ouvert
File
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

Accès ouvert
File
203 Téléchargements (Pure)

2 Terminé

tryptophane 2,3-dioxygénase
Wouters, J. (Responsable du Projet)
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. (Responsable du Projet)
1/10/07 → 30/09/10
Projet: Recherche

Physico-chimie et caractérisation (PC2)
Wouters, J. (!!Manager), Aprile, C. (!!Manager) & Fusaro, L. (!!Manager)
Plateforme technologique Caracterisation physico-chimiques
Equipement/installations: Plateforme technolgique

5 Participation à une conférence, un congrès

Heterocycles in Bio-organic Chemistry
Dolusic, E. (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
Dolusic, E. (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)
Dolusic, E. (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
Dolusic, E.
24/02/12
1 élément de Couverture média
Presse/Médias: Autre
USPJEH MLADOGA OGULINCA
Dolusic, E.
24/02/12
1 élément de Couverture média
Presse/Médias: Autre
Ogulinac Eduard Dolušić nadomak otkriću lijeka protiv raka
Dolusic, E.
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.
Molle, N. (Auteur)Wouters, J. (Promoteur), Dolusic, E. (Jury), Moineaux, L. (Jury), Fonder, G. (Jury) & Leherte, L. (Jury), 2012
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

@article{bd027a9d778741c289c68ed3e08f0d26,

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

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.",

author = "L. Pilotte and P. Larrieu and V. Stroobant and D. Colau and E. Dolu{\v s}i{\'c} and R. Fr{\'e}d{\'e}rick and {De Plaen}, E. and C. Uyttenhove and J. Wouters and B. Masereel and {Van Den Eynde}, B.J.",

year = "2012",

month = feb,

day = "14",

doi = "10.1073/pnas.1113873109",

language = "English",

volume = "109",

pages = "2497--2502",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "7",

}

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

TY - JOUR

T1 - Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase

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

Y1 - 2012/2/14

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.

UR - http://www.scopus.com/inward/record.url?scp=84857136779&partnerID=8YFLogxK

U2 - 10.1073/pnas.1113873109

DO - 10.1073/pnas.1113873109

M3 - Article

AN - SCOPUS:84857136779

SN - 0027-8424

VL - 109

SP - 2497

EP - 2502

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 7

ER -

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

Résumé

SDG des Nations Unies

Accès au document

Autres fichiers et liens

Empreinte digitale

Résultat de recherche

Projets

Équipement

Activités

Presse/médias

Thèses de l'étudiant

Contient cette citation