Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase.
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.
Ludwig Institute for Cancer Research, Brussels Branch, and de Duve Institute,  Université Catholique de Louvain, B-1200 Brussels,  Belgium.
Luc
L
Pilotte
Pierre
P
Larrieu
Vincent
V
Stroobant
Didier
D
Colau
Eduard
E
Dolusic
Raphaël
R
Frédérick
Etienne
E
De Plaen
Catherine
C
Uyttenhove
Johan
J
Wouters
Bernard
B
Masereel
Benoît J
BJ
Van den Eynde
D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000276:immunology*; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D014366:Tryptophan Oxygenase