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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.

No MeSH data available.


Related in: MedlinePlus

IDO1 is expressed in CD163+ TAMs in SPTCL but not in MF or LyP skin lesions. Double IHC staining for IDO1 (turquoise) and CD163 (red) showing (A and B) LyP lesions and (C and D) MF lesions with separate cells expressing either IDO1 or CD163 (10x, and 40x, respectively), (E and F) Double positive IDO1+/CD163+ TAMs are seen surrounding the periadipocytic SPTCL infiltrate like a protective wall (10x and 40x, respectively). Light hematoxylin counterstaining. (Scale bar 20 µm). TAM, tumor-associated macrophage.
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f0004: IDO1 is expressed in CD163+ TAMs in SPTCL but not in MF or LyP skin lesions. Double IHC staining for IDO1 (turquoise) and CD163 (red) showing (A and B) LyP lesions and (C and D) MF lesions with separate cells expressing either IDO1 or CD163 (10x, and 40x, respectively), (E and F) Double positive IDO1+/CD163+ TAMs are seen surrounding the periadipocytic SPTCL infiltrate like a protective wall (10x and 40x, respectively). Light hematoxylin counterstaining. (Scale bar 20 µm). TAM, tumor-associated macrophage.

Mentions: We next identified IDO1-expressing cells in the lymphoma microenvironment by performing double IHC and IF staining. Both techniques revealed that the cell types expressing IDO1 in the microenvironment differed between LyP, MF, and SPTCL. LyP and MF contained considerable numbers of CD163+ TAMs, but they did not express IDO1 (Figs. 4A–D, respectively). In SPTCL, CD163+ TAMs surrounding the subcutaneous malignant lymphocyte infiltrates expressed IDO1 (Fig. 4E–F). Also, a proportion of the morphologically malignant lymphocytes in SPTCL (Fig. 4E and ref. 16) and in MF expressed IDO1 (ca. 10%, Fig. 4D).Figure 4.


Biological and clinical significance of tryptophan-catabolizing enzymes in cutaneous T-cell lymphomas
IDO1 is expressed in CD163+ TAMs in SPTCL but not in MF or LyP skin lesions. Double IHC staining for IDO1 (turquoise) and CD163 (red) showing (A and B) LyP lesions and (C and D) MF lesions with separate cells expressing either IDO1 or CD163 (10x, and 40x, respectively), (E and F) Double positive IDO1+/CD163+ TAMs are seen surrounding the periadipocytic SPTCL infiltrate like a protective wall (10x and 40x, respectively). Light hematoxylin counterstaining. (Scale bar 20 µm). TAM, tumor-associated macrophage.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f0004: IDO1 is expressed in CD163+ TAMs in SPTCL but not in MF or LyP skin lesions. Double IHC staining for IDO1 (turquoise) and CD163 (red) showing (A and B) LyP lesions and (C and D) MF lesions with separate cells expressing either IDO1 or CD163 (10x, and 40x, respectively), (E and F) Double positive IDO1+/CD163+ TAMs are seen surrounding the periadipocytic SPTCL infiltrate like a protective wall (10x and 40x, respectively). Light hematoxylin counterstaining. (Scale bar 20 µm). TAM, tumor-associated macrophage.
Mentions: We next identified IDO1-expressing cells in the lymphoma microenvironment by performing double IHC and IF staining. Both techniques revealed that the cell types expressing IDO1 in the microenvironment differed between LyP, MF, and SPTCL. LyP and MF contained considerable numbers of CD163+ TAMs, but they did not express IDO1 (Figs. 4A–D, respectively). In SPTCL, CD163+ TAMs surrounding the subcutaneous malignant lymphocyte infiltrates expressed IDO1 (Fig. 4E–F). Also, a proportion of the morphologically malignant lymphocytes in SPTCL (Fig. 4E and ref. 16) and in MF expressed IDO1 (ca. 10%, Fig. 4D).Figure 4.

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