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Accumulation of an endogenous tryptophan-derived metabolite in colorectal and breast cancers.

Puccetti P, Fallarino F, Italiano A, Soubeyran I, MacGrogan G, Debled M, Velasco V, Bodet D, Eimer S, Veldhoen M, Prendergast GC, Platten M, Bessede A, Guillemin GJ - PLoS ONE (2015)

Bottom Line: We developed a monoclonal antibody targeting l-kynurenine as an in situ biomarker of IDO-1/-2 or TDO2 activity.Using Tissue Micro Array technology and immunostaining, colorectal and breast cancer patients were phenotyped based on l-kynurenine production.In colorectal cancer l-kynurenine was not unequivocally associated with IDO-1 expression, suggesting that the mere expression of tryptophan catabolic enzymes is not sufficiently informative for optimal immunotherapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.

ABSTRACT
Tumor immune escape mechanisms are being regarded as suitable targets for tumor therapy. Among these, tryptophan catabolism plays a central role in creating an immunosuppressive environment, leading to tolerance to potentially immunogenic tumor antigens. Tryptophan catabolism is initiated by either indoleamine 2,3-dioxygenase (IDO-1/-2) or tryptophan 2,3-dioxygenase 2 (TDO2), resulting in biostatic tryptophan starvation and l-kynurenine production, which participates in shaping the dynamic relationship of the host's immune system with tumor cells. Current immunotherapy strategies include blockade of IDO-1/-2 or TDO2, to restore efficient antitumor responses. Patients who might benefit from this approach are currently identified based on expression analyses of IDO-1/-2 or TDO2 in tumor tissue and/or enzymatic activity assessed by kynurenine/tryptophan ratios in the serum. We developed a monoclonal antibody targeting l-kynurenine as an in situ biomarker of IDO-1/-2 or TDO2 activity. Using Tissue Micro Array technology and immunostaining, colorectal and breast cancer patients were phenotyped based on l-kynurenine production. In colorectal cancer l-kynurenine was not unequivocally associated with IDO-1 expression, suggesting that the mere expression of tryptophan catabolic enzymes is not sufficiently informative for optimal immunotherapy.

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Overview of the tryptophan metabolism and the kynurenine pathway.IDO-1: Indoleamine 2,3-dioxygenase 1. IDO-2: Indoleamine 2,3-dioxygnease 2. TDO2: Tryptophan 2,3-dioxygenase. KATs: Kynurenine amino transferases. KMO: Kynurenine-3-monooxygenase. KYNU: Kynureninase. 3HAO: 3-hydroxyanthranilate oxygenase
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pone.0122046.g001: Overview of the tryptophan metabolism and the kynurenine pathway.IDO-1: Indoleamine 2,3-dioxygenase 1. IDO-2: Indoleamine 2,3-dioxygnease 2. TDO2: Tryptophan 2,3-dioxygenase. KATs: Kynurenine amino transferases. KMO: Kynurenine-3-monooxygenase. KYNU: Kynureninase. 3HAO: 3-hydroxyanthranilate oxygenase

Mentions: In mammals, tryptophan catabolism is a physiological means of preserving immune homeostasis and tolerance—including maternofetal tolerance—and avoiding acute and chronic hyper-inflammatory reactions and autoimmunity [2]. Tryptophan degradation is initiated by three different enzymes, namely, indoleamine 2,3-dioxygenase 1 (IDO-1), its paralogue IDO-2, and tryptophan 2,3-dioxygenase 2 (TDO2; mostly expressed in the liver) (Fig 1). All three enzymes induce biostatic tryptophan starvation that limits lymphocyte expansion, and produce several catabolites, collectively known as kynurenines [3]. l-kynurenine, an amino acid itself, is the first, stable tryptophan catabolite in this pathway. l-kynurenine induces T helper type-1 cell apoptosis [4], and can also act as an endogenous activator of the ligand-operated transcription factor aryl hydrocarbon receptor (AhR), thus altering immune responses [5, 6].


Accumulation of an endogenous tryptophan-derived metabolite in colorectal and breast cancers.

Puccetti P, Fallarino F, Italiano A, Soubeyran I, MacGrogan G, Debled M, Velasco V, Bodet D, Eimer S, Veldhoen M, Prendergast GC, Platten M, Bessede A, Guillemin GJ - PLoS ONE (2015)

Overview of the tryptophan metabolism and the kynurenine pathway.IDO-1: Indoleamine 2,3-dioxygenase 1. IDO-2: Indoleamine 2,3-dioxygnease 2. TDO2: Tryptophan 2,3-dioxygenase. KATs: Kynurenine amino transferases. KMO: Kynurenine-3-monooxygenase. KYNU: Kynureninase. 3HAO: 3-hydroxyanthranilate oxygenase
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4400104&req=5

pone.0122046.g001: Overview of the tryptophan metabolism and the kynurenine pathway.IDO-1: Indoleamine 2,3-dioxygenase 1. IDO-2: Indoleamine 2,3-dioxygnease 2. TDO2: Tryptophan 2,3-dioxygenase. KATs: Kynurenine amino transferases. KMO: Kynurenine-3-monooxygenase. KYNU: Kynureninase. 3HAO: 3-hydroxyanthranilate oxygenase
Mentions: In mammals, tryptophan catabolism is a physiological means of preserving immune homeostasis and tolerance—including maternofetal tolerance—and avoiding acute and chronic hyper-inflammatory reactions and autoimmunity [2]. Tryptophan degradation is initiated by three different enzymes, namely, indoleamine 2,3-dioxygenase 1 (IDO-1), its paralogue IDO-2, and tryptophan 2,3-dioxygenase 2 (TDO2; mostly expressed in the liver) (Fig 1). All three enzymes induce biostatic tryptophan starvation that limits lymphocyte expansion, and produce several catabolites, collectively known as kynurenines [3]. l-kynurenine, an amino acid itself, is the first, stable tryptophan catabolite in this pathway. l-kynurenine induces T helper type-1 cell apoptosis [4], and can also act as an endogenous activator of the ligand-operated transcription factor aryl hydrocarbon receptor (AhR), thus altering immune responses [5, 6].

Bottom Line: We developed a monoclonal antibody targeting l-kynurenine as an in situ biomarker of IDO-1/-2 or TDO2 activity.Using Tissue Micro Array technology and immunostaining, colorectal and breast cancer patients were phenotyped based on l-kynurenine production.In colorectal cancer l-kynurenine was not unequivocally associated with IDO-1 expression, suggesting that the mere expression of tryptophan catabolic enzymes is not sufficiently informative for optimal immunotherapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.

ABSTRACT
Tumor immune escape mechanisms are being regarded as suitable targets for tumor therapy. Among these, tryptophan catabolism plays a central role in creating an immunosuppressive environment, leading to tolerance to potentially immunogenic tumor antigens. Tryptophan catabolism is initiated by either indoleamine 2,3-dioxygenase (IDO-1/-2) or tryptophan 2,3-dioxygenase 2 (TDO2), resulting in biostatic tryptophan starvation and l-kynurenine production, which participates in shaping the dynamic relationship of the host's immune system with tumor cells. Current immunotherapy strategies include blockade of IDO-1/-2 or TDO2, to restore efficient antitumor responses. Patients who might benefit from this approach are currently identified based on expression analyses of IDO-1/-2 or TDO2 in tumor tissue and/or enzymatic activity assessed by kynurenine/tryptophan ratios in the serum. We developed a monoclonal antibody targeting l-kynurenine as an in situ biomarker of IDO-1/-2 or TDO2 activity. Using Tissue Micro Array technology and immunostaining, colorectal and breast cancer patients were phenotyped based on l-kynurenine production. In colorectal cancer l-kynurenine was not unequivocally associated with IDO-1 expression, suggesting that the mere expression of tryptophan catabolic enzymes is not sufficiently informative for optimal immunotherapy.

Show MeSH
Related in: MedlinePlus