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.

Cancer alters cell metabolism. How these changes are manifested in the metabolite cargo of cancer-derived extracellular vesicles (EVs) remains poorly understood. To explore these changes, EVs from prostate, cutaneous T-cell lymphoma (CTCL), colon cancer cell lines, and control EVs from their noncancerous counterparts were isolated by differential ultracentrifugation and analyzed by nanoparticle tracking analysis (NTA), electron microscopy (EM), Western blotting, and liquid chromatography-mass spectrometry (LC-MS). Although minor differences between the cancerous and non-cancerous cell-derived EVs were observed by NTA and Western blotting, the largest differences were detected in their metabolite cargo. Compared to EVs from noncancerous cells, cancer EVs contained elevated levels of soluble metabolites, e.g., amino acids and B vitamins. Two metabolites, proline and succinate, were elevated in the EV samples of all three cancer types. In addition, folate and creatinine were elevated in the EVs from prostate and CTCL cancer cell lines. In conclusion, we present the first evidence in vitro that the altered metabolism of different cancer cells is reflected in common metabolite changes in their EVs. These results warrant further studies on the significance and usability of this metabolic fingerprint in cancer.