Inhibiting tryptophan metabolism enhances interferon therapy in kidney cancer.

ABSTRACT: Renal cell carcinoma (RCC) is increasing in incidence, and a complete cure remains elusive. While immune-checkpoint antibodies are promising, interferon-based immunotherapy has been disappointing. Tryptophan metabolism, which produces immunosuppressive metabolites, is enhanced in RCC. Here we show indolamine-2,3-dioxygenase-1 (IDO1) expression, a kynurenine pathway enzyme, is increased not only in tumor cells but also in the microenvironment of human RCC compared to normal kidney tissues. Neither kynurenine metabolites nor IDO inhibitors affected the survival or proliferation of human RCC or murine renal cell adenocarcinoma (RENCA) cells in vitro. However, interferon-gamma (IFN?) induced high levels of IDO1 in both RCC and RENCA cells, concomitant with enhanced kynurenine levels in conditioned media. Induction of IDO1 by IFN? was weaker than by IFN?. Neither the IDO1 inhibitor methyl-thiohydantoin-DL-tryptophan (MTH-trp) nor IFN? alone inhibited RENCA tumor growth, however the combination of MTH-trp and IFN? reduced tumor growth compared to IFN?. Thus, the failure of IFN? therapy for human RCC is likely due to its inability to overcome the immunosuppressive environment created by increased IDO1. Based on our data, and given that IDO inhibitors are already in clinical trials for other malignancies, IFN? therapy with an IDO inhibitor should be revisited for RCC.

SUBMITTER: Trott JF 

PROVIDER: S-EPMC5341819 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature