THE ROLE OF INDOLEAMINE 2,3-DIOXYGENASE IN THE ANTITUMOR-ACTIVITY OF HUMAN INTERFERON-GAMMA IN-VIVO

We have studied the relationship between L-tryptophan metabolism and t he response to human IFN-gamma in 3 human ovarian cancer xenografts gr owing in nude mice. During IFN-gamma therapy all 3 tumours showed a pr ofound depletion in L-tryptophan and a corresponding rise in L-kynuren ine. The microenvironment surrounding the tumours was also depleted of L-tryptophan. The IfN-gamma-inducible enzyme indoleamine dioxygenase, IDO, was induced in treated tumours. While there was a variability in IDO mRNA expression in the different xenografts tested, in situ hybri dization showed that the gene was induced at all levels of the tumour, and not just the periphery. These results show that induction of IDO by IFN-gamma in vivo can metabolize L-tryptophan rapidly enough for it to become depleted, despite a continued supply of L-tryptophan from t he host. The IDO mRNA and protein remained induced after the L-tryptop han levels had returned to normal, suggesting that the gene may be pos t-transcriptionally regulated and/or the IDO co-factor supply may be l imited. Another IFN-gamma-inducible gene, tryptophanyl tRNA synthetase , was also induced in the tumour. It is possible that this enzyme, whi ch is responsible for synthesizing tryptophanyl tRNA, acts in a compen satory manner by allowing protein synthesis to continue despite low fr ee L-tryptophan concentrations. There was no correlation of the above parameters with the anti-tumour response to IFN-gamma, suggesting that other mechanisms must play a role. L-tryptophan depletion may be a co ntributor to a multifactorial growth inhibition of tumour cells follow ing IFN-gamma treatment, but cannot on its own explain their growth in hibition. (C) 1995 Wiley-Liss, Inc.