Limits...
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.

Show MeSH

Related in: MedlinePlus

Immunodetection of IDO-1 and l-Kynurenine in colorectal cancer samples.A and B, Representative micrographs of immunohistochemical stainings of paraffin-embedded colorectal cancer samples using specific antibodies targeting IDO-1 or l-kynurenine. On the up-right panel, graph represents IDO-1 immunoscore (obtained from 2 independent TMA cores) with % of IDO-1 positive patients. On the downright panel, scatter plot represents IDO-1 immunoscore over kynurenine immunoscore (C) Representative micrographs of IDO-1 and kynurenine immunostainings of immune cells from paraffin-embedded colorectal cancer samples.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4400104&req=5

pone.0122046.g003: Immunodetection of IDO-1 and l-Kynurenine in colorectal cancer samples.A and B, Representative micrographs of immunohistochemical stainings of paraffin-embedded colorectal cancer samples using specific antibodies targeting IDO-1 or l-kynurenine. On the up-right panel, graph represents IDO-1 immunoscore (obtained from 2 independent TMA cores) with % of IDO-1 positive patients. On the downright panel, scatter plot represents IDO-1 immunoscore over kynurenine immunoscore (C) Representative micrographs of IDO-1 and kynurenine immunostainings of immune cells from paraffin-embedded colorectal cancer samples.

Mentions: As l-kynurenine production is mostly dependent on IDO-1 activity, we investigated IDO-1 expression in the same cohort of CRC patients using IHC. IDO-1 was up regulated in 9 (13%) out of 69 samples (Fig 3A), a percentage similar to that reported by Gao et al [24], but lower than the 39% value found by an earlier study [14], which suggests significant variability among tumor specimens even of the same histotype. Similarly with l-kynurenine detection, no positive correlation could be established between IDO-1 expression and clinical data (grade and size of the tumor, lymph node invasion and metastases; data not shown). When present, IDO-1 was invariably expressed in the cytoplasm of tumor cells, but there were also instances of noticeable expression by cells from the microenvironment [24].


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)

Immunodetection of IDO-1 and l-Kynurenine in colorectal cancer samples.A and B, Representative micrographs of immunohistochemical stainings of paraffin-embedded colorectal cancer samples using specific antibodies targeting IDO-1 or l-kynurenine. On the up-right panel, graph represents IDO-1 immunoscore (obtained from 2 independent TMA cores) with % of IDO-1 positive patients. On the downright panel, scatter plot represents IDO-1 immunoscore over kynurenine immunoscore (C) Representative micrographs of IDO-1 and kynurenine immunostainings of immune cells from paraffin-embedded colorectal cancer samples.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0122046.g003: Immunodetection of IDO-1 and l-Kynurenine in colorectal cancer samples.A and B, Representative micrographs of immunohistochemical stainings of paraffin-embedded colorectal cancer samples using specific antibodies targeting IDO-1 or l-kynurenine. On the up-right panel, graph represents IDO-1 immunoscore (obtained from 2 independent TMA cores) with % of IDO-1 positive patients. On the downright panel, scatter plot represents IDO-1 immunoscore over kynurenine immunoscore (C) Representative micrographs of IDO-1 and kynurenine immunostainings of immune cells from paraffin-embedded colorectal cancer samples.
Mentions: As l-kynurenine production is mostly dependent on IDO-1 activity, we investigated IDO-1 expression in the same cohort of CRC patients using IHC. IDO-1 was up regulated in 9 (13%) out of 69 samples (Fig 3A), a percentage similar to that reported by Gao et al [24], but lower than the 39% value found by an earlier study [14], which suggests significant variability among tumor specimens even of the same histotype. Similarly with l-kynurenine detection, no positive correlation could be established between IDO-1 expression and clinical data (grade and size of the tumor, lymph node invasion and metastases; data not shown). When present, IDO-1 was invariably expressed in the cytoplasm of tumor cells, but there were also instances of noticeable expression by cells from the microenvironment [24].

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