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 (SPTCL n = 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 both IDO1 and TDO was 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.

KEYWORDS:

• Cutaneous T-cell lymphoma
• immunosuppressive microenvironment
• indoleamine 2,3-dioxygenase 1
• kynurenine
• tryptophan 2,3-dioxygenase

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

We are indebted to Mrs. Alli Tallqvist, Kaija Järvinen, and Nadine Nürnberger for their skillful technical assistance, Dr. Pilar García Muret for providing the FFPE tissues of six Spanish LyP patients, and Prof. Dr. Robert Gniadecki for providing the MyLa2000 cells.

Funding

This study was supported by funding from Instrumentarium Science Foundation (PM), K. Albin Johansson foundation (PM), Emil Aaltonen-foundation (PM), HUCH Research Grants (AR), Finska Läkaresällskapet (AR, PM), and the German Research Society (KFO262, KD, PJO). MEK is supported by Drs. Martin and Dorothy Spatz Charitable Foundation.