title: Biological and clinical significance of tryptophan-catabolizing enzymes in cutaneous T-cell lymphomas.
abstract: Indoleamine 2,3-deoxygenase 1 (IDO1) induces immune tolerance in the tumor microenvironment (TME) and is recognized as a potential therapeutic target. We studied the expression of both IDO1 and the related tryptophan 2,3-dioxygenase (TDO) in several different subtypes of cutaneous T-cell lymphoma (CTCL), and evaluated the kynurenine (KYN) pathway in the local TME and in patient sera. Specimens from the total of 90 CTCL patients, including mycosis fungoides (MF,n= 37), lymphomatoid papulosis (LyP,n= 36), primary cutaneous anaplastic large cell lymphoma (pcALCL,n= 4), subcutaneous panniculitis-like T-cell lymphoma (SPTCLn= 13), and 10 patients with inflammatory lichen ruber planus (LRP), were analyzed by immunohistochemistry (IHC), immunofluorescence (IF), quantitative PCR, and/or liquid chromatography-tandem mass spectrometry (LC-MS/MS). Three CTCL cell lines also were studied. Expression of bothIDO1andTDOwas upregulated in CTCL. In MF specimens and in the MF cell line MyLa2000, IDO1 expression exceeded that of TDO, whereas the opposite was true for LyP, ALCL, and corresponding Mac1/2A cell lines. The spectrum of IDO1-expressing cell types differed among CTCL subtypes and was reflected in the clinical behavior. In MF, SPTCL, and LyP, IDO1 was expressed by malignant cells and by CD33+myeloid-derived suppressor cells, whereas in SPTCL CD163+tumor-associated macrophages also expressed IDO1. Significantly elevated serum KYN/Trp ratios were found in patients with advanced stages of MF. Epacadostat, an IDO1 inhibitor, induced a clear decrease in KYN concentration in cell culture. These results show the importance of IDO1/TDO-induced immunosuppression in CTCL and emphasize its role as a new therapeutic target.
authors.affiliation: Department of Dermatology and Allergology, University of Helsinki and Helsinki University Central Hospital , Helsinki, Finland.
authors.forename: Pilvi
authors.initials: P
authors.lastname: Maliniemi
authors.affiliation: Department of Dermatology and Allergology, University of Helsinki and Helsinki University Central Hospital , Helsinki, Finland.
authors.forename: Kirsi
authors.identifier: 0000-0001-6243-9850
authors.initials: K
authors.lastname: Laukkanen
authors.affiliation: Department of Dermatology and Allergology, University of Helsinki and Helsinki University Central Hospital , Helsinki, Finland.
authors.forename: Liisa
authors.identifier: 0000-0003-4828-1553
authors.initials: L
authors.lastname: Väkevä
authors.affiliation: Institute of Functional Genomics, University of Regensburg , Regensburg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Dettmer
authors.affiliation: Department of Dermatology and Allergology, University of Helsinki and Helsinki University Central Hospital , Helsinki, Finland.
authors.forename: Tuomas
authors.initials: T
authors.lastname: Lipsanen
authors.affiliation: Department of Dermatology and Allergology, University of Helsinki and Helsinki University Central Hospital , Helsinki, Finland.
authors.forename: Leila
authors.initials: L
authors.lastname: Jeskanen
authors.affiliation: ImmuSmol , Pessac, France.
authors.forename: Alban
authors.initials: A
authors.lastname: Bessede
authors.affiliation: Institute of Functional Genomics, University of Regensburg , Regensburg, Germany.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oefner
authors.affiliation: Department of Pathology, Rhode Island Hospital, Providence, RI, USA; Department of Dermatology, Boston University School of Medicine and Roger Williams Medical Center, Providence, RI, USA.
authors.forename: Marshall E
authors.initials: ME
authors.lastname: Kadin
authors.affiliation: Department of Dermatology and Allergology, University of Helsinki and Helsinki University Central Hospital , Helsinki, Finland.
authors.forename: Annamari
authors.identifier: 0000-0003-4335-0396
authors.initials: A
authors.lastname: Ranki
keywords: Cutaneous T-cell lymphoma; immunosuppressive microenvironment; indoleamine 2,3-dioxygenase 1; kynurenine; tryptophan 2,3-dioxygenase