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

Pilotte, Luc;Larrieu, Pierre;Stroobant, Vincent;Colau, Didier;Van den Eynde, Benoit;et.al.
(2012) Proceedings of the National Academy of Sciences of the United States of America — Vol. 109, n° 7, p. 2497-2502 (2012)

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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., Dolusic, E., Frédérick, R., De Plaen, E., Uyttenhove, C., Wouters, J., Masereel, B., & Van den Eynde, B. (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 (Original work published 2012)