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.
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Publication status||Published - 14 Feb 2012|
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