IDO-Mediated Tryptophan Degradation in the Pathogenesis of Malignant Tumor Disease

Our plain-English summary of IDO-Mediated Tryptophan Degradation in the Pathogenesis of Malignant Tumor Disease, by R. Sucher, K. Kurz, G. Weiss, et al (International Journal of Tryptophan Research, 2010).

The study

• Authors: R. Sucher, K. Kurz, G. Weiss, R. Margreiter, D. Fuchs, G. Brandacher
• Journal: International Journal of Tryptophan Research
• Published: 2010;3:113-20
• Cited by: 42 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Immune escape is a fundamental trait of cancer in which the Th1-type cytokine interferon- γ (IFN-γ) seems to play a key role. Among other tumoricidal biochemical pathways, IFN-γ induces the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) in a variety of cells including macrophages, dendritic cells (DCs) and tumor cells. IDO activity has been shown to reflect the extent and the course in a plethora of malignancies including prostate, colorectal, pancreatic, cervical, endometrial, gastric, lung, bladder, ovarian, esophageal and renal cell carcinomas, glioblastomas, mesotheliomas, and melanomas. Furthermore IDO activity during malignant tumor diseases seems to be part of the tumoricidal immune defense strategy, which in the long run is detrimental to the host, when tryptophan deprivation and production of pro-apoptotic tryptophan catabolites counteract T-cell responsiveness.

In plain English

This article was a review, not an original study. The authors summarized published research on indoleamine 2,3-dioxygenase (IDO), an enzyme that breaks down the amino acid tryptophan. The article did not describe how the reviewed studies were chosen. The authors listed mesotheliomas among many cancers with reported IDO activity but gave no mesothelioma data and did not discuss asbestos. A table of other studies linked higher IDO expression with reduced overall survival in cancers such as malignant melanoma, endometrial carcinoma and osteosarcoma. In renal cell carcinoma, a cited study linked IDO expression in tumor endothelial cells with long-term survival. The authors described two proposed ways IDO may weaken immune responses: depriving T-cells of tryptophan, and tryptophan breakdown products. In a cited mouse study, the IDO-blocking drug 1-MT slowed but did not prevent tumor growth. The authors concluded that there is clear evidence IDO interferes with immune regulation, supporting clinical testing of IDO inhibitors to improve anticancer immunotherapy, alongside radiation and chemotherapy. They noted that the effects of one such drug, D-1-MT, in humans were still unknown.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of experimental and clinical studies; no original data
• Who was studied: No study population of its own. The review covered published studies of IDO in many human cancers, with mesotheliomas named only in a list.
• Exposure: No asbestos or fiber exposure. The subject was the activity of the tryptophan-degrading enzyme IDO, which is induced by interferon-gamma.
• Main results:
  • In the reviewed studies, IDO expression correlated with poor overall survival in endometrial cancer, ovarian cancer and high-grade osteosarcomas. These were findings of other studies (references 34 to 36).
  • In contrast, a cited study found that IDO expression in tumor endothelial cells of patients with renal cell carcinoma correlated with long-term survival.
  • Mesotheliomas were mentioned only as one of many cancers in which IDO activity or expression has been reported. Mesothelioma does not appear in the survival table, and no mesothelioma-specific data were given.
  • Two main theories were described for how IDO suppresses immunity: involvement of tryptophan metabolites, or starving cells of tryptophan.
  • In a cited mouse breast cancer model, the IDO inhibitor 1-MT appeared only able to slow tumor growth, not prevent it.
• The authors' conclusion: The authors concluded that there is clear evidence IDO interferes with immune regulation and contributes to tumors evading the immune system. They said this offers a rationale for clinical investigation of IDO inhibitors to increase the efficacy of anticancer immunotherapy, in addition to conventional radiation and chemotherapy.
• Limitations the authors state:
  • The authors stated it was currently unclear to what extent tryptophan starvation accounts for IDO-mediated immunosuppression.
  • The authors stated that, although D-1-MT had entered clinical trials, its therapeutic effects in humans had not yet been established.

Topics

Medical terms in this study, explained in our Lexicon: Cytokine, Macrophage, Carcinoma, Mesothelioma.

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