Inhibiting tryptophan metabolism enhances interferon therapy in kidney cancer.

Josephine F Trott,Ashley Graef,Omran Abu Aboud,Benjamin Stewart,Grace Berryhill,Aaron L Sarver,Robert H Weiss,Ching-Hsien Chen,Russell C Hovey,Jeffrey Kim,Katie Anderson,Jaime F Modiano,Francisco Uzal,Hiromi Wettersten

doi:10.18632/oncotarget.11658

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 (IFNγ) induced high levels of IDO1 in both RCC and RENCA cells, concomitant with enhanced kynurenine levels in conditioned media. Induction of IDO1 by IFNα was weaker than by IFNγ. Neither the IDO1 inhibitor methyl-thiohydantoin-DL-tryptophan (MTH-trp) nor IFNα alone inhibited RENCA tumor growth, however the combination of MTH-trp and IFNα reduced tumor growth compared to IFNα. Thus, the failure of IFNα 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, IFNα therapy with an IDO inhibitor should be revisited for RCC.

Highlights

Kidney cancer is one of the few malignancies that show an increasing incidence in the United States, possibly due to the prevalence of obesity and the metabolic syndrome in the Western world [1, 2]
We show that growth of several human Renal cell carcinoma (RCC) cell lines as well as renal cell adenocarcinoma (RENCA) cells incubated in the presence of IDO inhibitors, kynurenine, or its metabolites, is not altered in vitro, yet growth of RENCA tumors in immune-competent mice in vivo is attenuated when IFNα is administered concurrently with the competitive IDO1 and IDO2 inhibitor methylthiohydantoin-DL-tryptophan (MTH-trp)
Our results suggest that the mechanism of this effect is associated with the production of IDO1 by endothelial, tumor and CD68+ immune cells leading to tryptophan catabolism into kynurenine, which can be inhibited by MTH-trp

Summary

Introduction

Kidney cancer is one of the few malignancies that show an increasing incidence in the United States, possibly due to the prevalence of obesity and the metabolic syndrome in the Western world [1, 2].

Methods

Results

Conclusion