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

55 Downloads (Pure)

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

Access to Document

10.1073/pnas.1113873109

PNAS 2012 finalFinal published version, 775 KB

Link to publication in Scopus

Fingerprint Dive into the research topics of 'Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase'. Together they form a unique fingerprint.

Projects

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

Equipment

Physical Chemistry and characterization(PC2)

Johan Wouters (Manager) & Carmela Aprile (Manager)

Technological Platform Physical Chemistry and characterization

Facility/equipment: Technological Platform

Activities

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

Press / Media

Mladi Ogulinac u ekipi koja je na tragu lijeka protiv raka

Eduard Dolusic

24/02/12

1 item of Media coverage

Press/Media: Other

USPJEH MLADOGA OGULINCA

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

Student Theses

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.

@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, 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

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

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

SN - 0027-8424

IS - 7

ER -