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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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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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, no. 7, pp. 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.

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

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3-ALKENYL INDOLES AS TRYPTOPHAN 2,3-DIOXYGENASE INHIBITORS FOR THE ENHANCEMENT OF CANCER IMMUNOTHERAPY