title: 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 (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.
authors: School of Medicine, Division of Nephrology, University of California Davis, Davis, CA, USA.|Department of Animal Science, University of California Davis, Davis, CA, USA.
authors: Josephine F
authors: JF
authors: Trott
authors: School of Medicine, Division of Nephrology, University of California Davis, Davis, CA, USA.
authors: Jeffrey
authors: J
authors: Kim
authors: School of Medicine, Division of Nephrology, University of California Davis, Davis, CA, USA.
authors: Omran
authors: O
authors: Abu Aboud
authors: School of Medicine, Division of Nephrology, University of California Davis, Davis, CA, USA.|Sanford Consortium for Regenerative Medicine, UC San Diego, La Jolla, CA, USA.
authors: Hiromi
authors: H
authors: Wettersten
authors: Biosciences and Biotechnology Division, Lawrence Livermore National Laboratory, Livermore, CA, USA.
authors: Benjamin
authors: B
authors: Stewart
authors: Department of Animal Science, University of California Davis, Davis, CA, USA.
authors: Grace
authors: G
authors: Berryhill
authors: California Animal Health and Food Safety Lab, School of Veterinary Medicine, University of California, Davis, San Bernardino, CA, USA.
authors: Francisco
authors: F
authors: Uzal
authors: Department of Animal Science, University of California Davis, Davis, CA, USA.
authors: Russell C
authors: RC
authors: Hovey
authors: School of Medicine, Division of Nephrology, University of California Davis, Davis, CA, USA.
authors: Ching-Hsien
authors: CH
authors: Chen
authors: Animal Cancer Care and Research Program, College of Veterinary Medicine, University of Minnesota, St Paul, MN, USA.|Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN, USA.|Masonic Cancer Center, Minneapolis, MN, USA.
authors: Katie
authors: K
authors: Anderson
authors: Animal Cancer Care and Research Program, College of Veterinary Medicine, University of Minnesota, St Paul, MN, USA.|Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN, USA.|Masonic Cancer Center, Minneapolis, MN, USA.
authors: Ashley
authors: A
authors: Graef
authors: Animal Cancer Care and Research Program, College of Veterinary Medicine, University of Minnesota, St Paul, MN, USA.|Masonic Cancer Center, Minneapolis, MN, USA.
authors: Aaron L
authors: AL
authors: Sarver
authors: Animal Cancer Care and Research Program, College of Veterinary Medicine, University of Minnesota, St Paul, MN, USA.|Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN, USA.|Masonic Cancer Center, Minneapolis, MN, USA.|Center for Immunology, Minneapolis, MN, USA.|Stem Cell Institute University of Minnesota, Minneapolis, MN, USA.
authors: Jaime F
authors: JF
authors: Modiano
authors: School of Medicine, Division of Nephrology, University of California Davis, Davis, CA, USA.|Comprehensive Cancer Center, University of California Davis, Davis, CA, USA.|Medical Service, VA Northern California Health Care System, Sacramento, CA, USA, USA.
authors: Robert H
authors: RH
authors: Weiss
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors*; D007211:Indoles / Q000494:pharmacology; D016898:Interferon-alpha / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D013867:Thiohydantoins / Q000494:pharmacology; D014364:Tryptophan / Q000187:drug effects / Q000378:metabolism*
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007211:Indoles; D016898:Interferon-alpha; D013867:Thiohydantoins; C500233:methyl-thiohydantoin-tryptophan; D014364:Tryptophan
keywords: 3-dioxygenase; indolamine-2; interferon-alpha; kynurenine; renal cell carcinoma; tryptophan