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

Fingerprint

Cite this

Pilotte, L., Larrieu, P., Stroobant, V., Colau, D., Dolušić, E., Frédérick, R., ... 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. Dolušić 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 = "2",

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