Inhibiting tryptophan metabolism enhances interferon therapy in kidney cancer

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

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)66540-66557
Number of pages18
JournalOncotarget
Volume7
Issue number41
DOIs
StatePublished - Jan 1 2016

Fingerprint

Kidney Neoplasms
Renal Cell Carcinoma
Tryptophan
Interferons
Indoleamine-Pyrrole 2,3,-Dioxygenase
Interferon-gamma
Kynurenine
Therapeutics
Immunosuppressive Agents
Neoplasms
Conditioned Culture Medium
Growth
Immunotherapy
Clinical Trials
Kidney
Survival
Antibodies

Keywords

  • Indolamine-2,3-dioxygenase
  • Interferon-alpha
  • Kynurenine
  • Renal cell carcinoma
  • Tryptophan

Cite this

Trott, J. F., Kim, J., Aboud, O. A., Wettersten, H., Stewart, B., Berryhill, G., ... Weiss, R. H. (2016). Inhibiting tryptophan metabolism enhances interferon therapy in kidney cancer. Oncotarget, 7(41), 66540-66557. https://doi.org/10.18632/oncotarget.11658

Inhibiting tryptophan metabolism enhances interferon therapy in kidney cancer. / Trott, Josephine F.; Kim, Jeffrey; Aboud, Omran Abu; Wettersten, Hiromi; Stewart, Benjamin; Berryhill, Grace; Uzal, Francisco; Hovey, Russell C.; Chen, Ching Hsien; Anderson, Katie; Graef, Ashley; Sarver, Aaron L; Modiano, Jaime; Weiss, Robert H.

In: Oncotarget, Vol. 7, No. 41, 01.01.2016, p. 66540-66557.

Research output: Contribution to journalArticle

Trott, JF, Kim, J, Aboud, OA, Wettersten, H, Stewart, B, Berryhill, G, Uzal, F, Hovey, RC, Chen, CH, Anderson, K, Graef, A, Sarver, AL, Modiano, J & Weiss, RH 2016, 'Inhibiting tryptophan metabolism enhances interferon therapy in kidney cancer', Oncotarget, vol. 7, no. 41, pp. 66540-66557. https://doi.org/10.18632/oncotarget.11658
Trott JF, Kim J, Aboud OA, Wettersten H, Stewart B, Berryhill G et al. Inhibiting tryptophan metabolism enhances interferon therapy in kidney cancer. Oncotarget. 2016 Jan 1;7(41):66540-66557. https://doi.org/10.18632/oncotarget.11658
Trott, Josephine F. ; Kim, Jeffrey ; Aboud, Omran Abu ; Wettersten, Hiromi ; Stewart, Benjamin ; Berryhill, Grace ; Uzal, Francisco ; Hovey, Russell C. ; Chen, Ching Hsien ; Anderson, Katie ; Graef, Ashley ; Sarver, Aaron L ; Modiano, Jaime ; Weiss, Robert H. / Inhibiting tryptophan metabolism enhances interferon therapy in kidney cancer. In: Oncotarget. 2016 ; Vol. 7, No. 41. pp. 66540-66557.
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