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Front Immunol. 2015 Jan 12;5:673. doi: 10.3389/fimmu.2014.00673. eCollection 2014.

Cancer Immunotherapy by Targeting IDO1/TDO and Their Downstream Effectors.

Author information

1
Neurology Clinic, University Hospital Heidelberg and National Center for Tumor Diseases , Heidelberg , Germany ; DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ) , Heidelberg , Germany.
2
DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ) , Heidelberg , Germany.
3
Neurology Clinic, University Hospital Heidelberg and National Center for Tumor Diseases , Heidelberg , Germany ; DKTK Clinical Cooperation Unit Neurooncology, German Cancer Research Center (DKFZ) , Heidelberg , Germany.

Abstract

The tryptophan (TRP) to kynurenine (KYN) metabolic pathway is now firmly established as a key regulator of innate and adaptive immunity. A plethora of preclinical models suggests that this immune tolerance pathway - driven by the key and rate-limiting enzymes indoleamine-2,3-dioxygenase and TRP-2,3-dioxygenase - is active in cancer immunity, autoimmunity, infection, transplant rejection, and allergy. Drugs targeting this pathway, specifically indoleamine-2,3-dioxygenase, are already in clinical trials with the aim at reverting cancer-induced immunosuppression. In the past years, there has been an increase in our understanding of the regulation and downstream mediators of TRP metabolism, such as the aryl hydrocarbon receptor as a receptor for KYN and kynurenic acid. This more detailed understanding will expand our opportunities to interfere with the pathway therapeutically on multiple levels. Here, we discuss the perspective of targeting TRP metabolism at these different levels based on reviewing recent insight into the regulation of TRP metabolism and its downstream effectors.

KEYWORDS:

AhR; IDO; TDO; tryptophan metabolism; tumor immunity

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