Accumulation of an endogenous tryptophan-derived metabolite in colorectal and breast cancers.
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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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PubMed Central - PubMed
Affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
ABSTRACT
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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. Related in: MedlinePlus |
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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]. |
View Article: PubMed Central - PubMed
Affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.