Amino Acid-Metabolizing Enzymes in Advanced High-Grade Serous Ovarian Cancer Patients: Value of Ascites as Biomarker Source and Role for IL4I1 and IDO1.

Autor: Grobben Y; Oncolines B.V., 5349 AB Oss, The Netherlands., den Ouden JE; Radboud Institute for Health Sciences, Radboud University Medical Center, Obstetrics and Gynecology, 6525 GA Nijmegen, The Netherlands., Aguado C; Laboratory of Oncology, Pangaea Oncology, Dexeus University Hospital, 08028 Barcelona, Spain., van Altena AM; Radboud Institute for Health Sciences, Radboud University Medical Center, Obstetrics and Gynecology, 6525 GA Nijmegen, The Netherlands., Kraneveld AD; Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands., Zaman GJR; Oncolines B.V., 5349 AB Oss, The Netherlands.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2023 Jan 31; Vol. 15 (3). Date of Electronic Publication: 2023 Jan 31.
DOI: 10.3390/cancers15030893
Abstrakt: The molecular mechanisms contributing to immune suppression in ovarian cancer are not well understood, hampering the successful application of immunotherapy. Amino acid-metabolizing enzymes are known to contribute to the immune-hostile environment of various tumors through depletion of amino acids and production of immunosuppressive metabolites. We aimed to collectively evaluate the activity of these enzymes in high-grade serous ovarian cancer patients by performing targeted metabolomics on plasma and ascites samples. Whereas no indication was found for enhanced l-arginine or l-glutamine metabolism by immunosuppressive enzymes in ovarian cancer patients, metabolism of l-tryptophan by indoleamine 2,3-dioxygenase 1 (IDO1) was significantly elevated compared to healthy controls. Moreover, high levels of l-phenylalanine- and l-tyrosine-derived metabolites associated with interleukin 4 induced 1 (IL4I1) activity were found in ovarian cancer ascites samples. While l-tryptophan is a major substrate of both IDO1 and IL4I1, only its enhanced conversion into l-kynurenine by IDO1 could be detected, despite the observed activity of IL4I1 on its other substrates. In ascites of ovarian cancer patients, metabolite levels were higher compared to those in plasma, demonstrating the value of utilizing this fluid for biomarker identification. Finally, elevated metabolism of l-phenylalanine and l-tyrosine by IL4I1 correlated with disease stage, pointing towards a potential role for IL4I1 in ovarian cancer progression.
Competing Interests: G.J.R. Zaman is managing director and founder of Oncolines B.V. The other authors have no potential conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
Databáze: MEDLINE
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