Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase.
Proc Natl Acad Sci U S A
; 109(7): 2497-502, 2012 Feb 14.
Article
em En
| MEDLINE
| ID: mdl-22308364
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Triptofano Oxigenase
/
Neoplasias
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article