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Biological and clinical significance of tryptophan-catabolizing enzymes in cutaneous T-cell lymphomas

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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.

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Relative frequencies of IDO1 and TDO expression in LRP and in each CTCL subgroup. The shade code indicates the percentage of the mononuclear cells expressing the given marker; +10–25% (light gray), ++ 26–50% (gray), and +++ >50% (dark gray).
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f0002: Relative frequencies of IDO1 and TDO expression in LRP and in each CTCL subgroup. The shade code indicates the percentage of the mononuclear cells expressing the given marker; +10–25% (light gray), ++ 26–50% (gray), and +++ >50% (dark gray).

Mentions: Immunohistochemical (IHC) analysis of formalin-fixed paraffin-embedded (FFPE) sections revealed protein expression of IDO1 and TDO to be substantially expressed in all studied CTCL subgroups (Fig. 2). Inflammatory or non-malignant cells accounted mostly for IDO1 expression (Fig. 3A–C). In MF, approximately 10% of morphologically malignant lymphocytes expressed IDO1, whereas IDO1-positive macrophages often surrounded the malignant cells (Fig. 3B). Interestingly, TDO expression dominated especially in LyP and ALCL (Fig. 2B). TDO was expressed by most of the large atypical cells in the inflammatory infiltrate in LyP (Fig. 3D) as well as in malignant lymphocytes in Pautrier microabscesses of MF (Fig. 2E). In SPCTL, TDO was also expressed by the malignant cells surrounding the adipocytes (Fig. 3F).Figure 2.


Biological and clinical significance of tryptophan-catabolizing enzymes in cutaneous T-cell lymphomas
Relative frequencies of IDO1 and TDO expression in LRP and in each CTCL subgroup. The shade code indicates the percentage of the mononuclear cells expressing the given marker; +10–25% (light gray), ++ 26–50% (gray), and +++ >50% (dark gray).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5384345&req=5

f0002: Relative frequencies of IDO1 and TDO expression in LRP and in each CTCL subgroup. The shade code indicates the percentage of the mononuclear cells expressing the given marker; +10–25% (light gray), ++ 26–50% (gray), and +++ >50% (dark gray).
Mentions: Immunohistochemical (IHC) analysis of formalin-fixed paraffin-embedded (FFPE) sections revealed protein expression of IDO1 and TDO to be substantially expressed in all studied CTCL subgroups (Fig. 2). Inflammatory or non-malignant cells accounted mostly for IDO1 expression (Fig. 3A–C). In MF, approximately 10% of morphologically malignant lymphocytes expressed IDO1, whereas IDO1-positive macrophages often surrounded the malignant cells (Fig. 3B). Interestingly, TDO expression dominated especially in LyP and ALCL (Fig. 2B). TDO was expressed by most of the large atypical cells in the inflammatory infiltrate in LyP (Fig. 3D) as well as in malignant lymphocytes in Pautrier microabscesses of MF (Fig. 2E). In SPCTL, TDO was also expressed by the malignant cells surrounding the adipocytes (Fig. 3F).Figure 2.

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus