Inhibiting tryptophan metabolism enhances interferon therapy in kidney cancer
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Josephine F. Trott1,2, Jeffrey Kim1, Omran Abu Aboud1, Hiromi Wettersten1,12, Benjamin Stewart4, Grace Berryhill2, Francisco Uzal5, Russell C. Hovey2, Ching-Hsien Chen1, Katie Anderson6,7,8, Ashley Graef6,7,8, Aaron L Sarver6,8, Jaime F. Modiano6,7,8,9,10 and Robert H. Weiss1,3,11
1 School of Medicine, Division of Nephrology, University of California Davis, Davis, CA, USA
2 Department of Animal Science, University of California Davis, Davis, CA, USA
3 Comprehensive Cancer Center, University of California Davis, Davis, CA, USA
4 Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA, USA
5 California Animal Health and Food Safety Lab, School of Veterinary Medicine, University of California, Davis, San Bernardino, CA, USA
6 Animal Cancer Care and Research Program, College of Veterinary Medicine, University of Minnesota, St Paul, MN, USA
7 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN, USA
8 Masonic Cancer Center, Minneapolis, MN, USA
9 Center for Immunology, Minneapolis, MN, USA
10 Stem Cell Institute University of Minnesota, Minneapolis, MN, USA
11 Medical Service, VA Northern California Health Care System, Sacramento, CA, USA, USA
12 Sanford Consortium for Regenerative Medicine, UC San Diego, La Jolla, CA, USA
Robert H. Weiss , email:
Keywords: tryptophan, kynurenine, renal cell carcinoma, interferon-alpha, indolamine-2,3-dioxygenase
Received: July 13, 2016 Accepted: August 01, 2016 Published: August 27, 2016
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.
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