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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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CD33+/IDO1+ expressing MDSCs are found in CTCL. (A) Double immunofluorescence staining of CD33 (red) and IDO1 (green) in typical LyP, MF, and SPTCL specimens. The top panel row shows a LyP tissue section with many strong double positive IDO1+/CD33+ cells (yellow) and some single positive IDO1+ or CD33+ cells. The second panel row shows an MF tissue section with cells either positive for IDO1+ or CD33+ as well as a few double positive IDO1+/CD33+ cells at lower right. The third panel row from top shows a SPTCL with double positive IDO1+/CD33+ cells as well as single positive cells (40x). In addition, IDO1 is expressed by both (B) CD30-positive and (C) CD30-negative cells in LyP (40x magnification). (Scale bar 20 µm).
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f0005: CD33+/IDO1+ expressing MDSCs are found in CTCL. (A) Double immunofluorescence staining of CD33 (red) and IDO1 (green) in typical LyP, MF, and SPTCL specimens. The top panel row shows a LyP tissue section with many strong double positive IDO1+/CD33+ cells (yellow) and some single positive IDO1+ or CD33+ cells. The second panel row shows an MF tissue section with cells either positive for IDO1+ or CD33+ as well as a few double positive IDO1+/CD33+ cells at lower right. The third panel row from top shows a SPTCL with double positive IDO1+/CD33+ cells as well as single positive cells (40x). In addition, IDO1 is expressed by both (B) CD30-positive and (C) CD30-negative cells in LyP (40x magnification). (Scale bar 20 µm).

Mentions: Furthermore, we found CD33+ myeloid derived suppressor cells (MDSCs) to express IDO1 in all studied CTCL subtypes (Fig. 5A). In the inflammatory infiltrates of some LyP samples, up to 30% of the cells were IDO1+ MDSCs (Fig. 5A, upper panel), clearly exceeding the number of double-positive cells in MF (Fig. 5A, middle panel). Interestingly, in some MF specimens the IDO1-expressing cells were CD33-negative. This indicates the presence of yet another IDO1-expressing cell population in MF awaiting identification. Double and single positive cells for IDO1 and CD33 were found to occur frequently in SPTCL (Fig. 5A, lower panel). In LyP, IDO1 was expressed only by a limited number of CD30+ cells (red) (Fig. 5B), whereas other cell types in the TME accounted mostly for IDO1 expression (green) (Fig. 5C).Figure 5.


Biological and clinical significance of tryptophan-catabolizing enzymes in cutaneous T-cell lymphomas
CD33+/IDO1+ expressing MDSCs are found in CTCL. (A) Double immunofluorescence staining of CD33 (red) and IDO1 (green) in typical LyP, MF, and SPTCL specimens. The top panel row shows a LyP tissue section with many strong double positive IDO1+/CD33+ cells (yellow) and some single positive IDO1+ or CD33+ cells. The second panel row shows an MF tissue section with cells either positive for IDO1+ or CD33+ as well as a few double positive IDO1+/CD33+ cells at lower right. The third panel row from top shows a SPTCL with double positive IDO1+/CD33+ cells as well as single positive cells (40x). In addition, IDO1 is expressed by both (B) CD30-positive and (C) CD30-negative cells in LyP (40x magnification). (Scale bar 20 µm).
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f0005: CD33+/IDO1+ expressing MDSCs are found in CTCL. (A) Double immunofluorescence staining of CD33 (red) and IDO1 (green) in typical LyP, MF, and SPTCL specimens. The top panel row shows a LyP tissue section with many strong double positive IDO1+/CD33+ cells (yellow) and some single positive IDO1+ or CD33+ cells. The second panel row shows an MF tissue section with cells either positive for IDO1+ or CD33+ as well as a few double positive IDO1+/CD33+ cells at lower right. The third panel row from top shows a SPTCL with double positive IDO1+/CD33+ cells as well as single positive cells (40x). In addition, IDO1 is expressed by both (B) CD30-positive and (C) CD30-negative cells in LyP (40x magnification). (Scale bar 20 µm).
Mentions: Furthermore, we found CD33+ myeloid derived suppressor cells (MDSCs) to express IDO1 in all studied CTCL subtypes (Fig. 5A). In the inflammatory infiltrates of some LyP samples, up to 30% of the cells were IDO1+ MDSCs (Fig. 5A, upper panel), clearly exceeding the number of double-positive cells in MF (Fig. 5A, middle panel). Interestingly, in some MF specimens the IDO1-expressing cells were CD33-negative. This indicates the presence of yet another IDO1-expressing cell population in MF awaiting identification. Double and single positive cells for IDO1 and CD33 were found to occur frequently in SPTCL (Fig. 5A, lower panel). In LyP, IDO1 was expressed only by a limited number of CD30+ cells (red) (Fig. 5B), whereas other cell types in the TME accounted mostly for IDO1 expression (green) (Fig. 5C).Figure 5.

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