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Indoleamine 2,3-dioxygenase is highly expressed in human adult T-cell leukemia/lymphoma and chemotherapy changes tryptophan catabolism in serum and reduced activity
Leukemia Research, 1, 33, pages 39 - 45
Adult T-cell leukemia/lymphoma (ATLL) is caused by human T-cell lymphotropic virus type 1 (HTLV-1). Indoleamine 2,3-dioxygenase (IDO), the l-tryptophan (l-TRP)-degrading enzyme, plays a key role in the powerful immunomodulatory effects of several different types of immune cells. In this study, we investigated the IDO expression in ATLL cells and the effect of chemotherapy on IDO-initiating l-TRP catabolism in patients with ATLL. Serum l-kynurenine (l-KYN) concentrations, l-KYN/l-TRP ratio, and the level of IDO mRNA expression in ATLL cells were significantly increased in ATLL patients compared to those in healthy and HTLV-positive carrier subjects. On the other hand, l-TRP level was significantly decreased in ATLL patients compared to that in healthy subjects. In the immunohistochemical staining, IDO was strongly expressed in cytoplasm of ATLL cells. Interestingly, serum l-KYN as well as soluble IL-2 receptor concentrations was significantly reduced, and l-TRP concentrations were significantly increased after chemotherapy. These data provide evidence that IDO is highly expressed in ATLL cells, and that IDO-initiating l-TRP catabolism changes with chemotherapy.
Keywords: Indoleamin 2,3-dioxgenase, l-Tryptophan, l-Kynurenine, Adult T-cell leukemia, Immunohistochemistry.
Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell neoplasm that develops in a small population of human T-cell lymphotropic virus type 1 (HTLV-1)-infected individuals and is characterized by mostly CD4+ and CD25+ mature T-cell phenotypes, and onsets at middle age or later , , , and . ATLL has a very poor prognosis, and the median survival time of patients with the acute and lymphoma subtypes of ATLL is less than 1 year. Further, there is no effective therapy for ATLL at present. Although conventional chemotherapies do not appear to prolong the life of patients with ATLL , , and , which is mainly due to severe infection and drug resistance, spontaneous tumor regression has been described in some ATLL patients  and  probably because of the immune response against ATLL-associated antigens  and . Although the exact mechanism of immune modulation in ATLL remains unknown, some previous reports have provided important clues. Such ATLL cells are thought to suppress the immune response via expression of immunoregulatory molecules on their surfaces and production of immunosuppressive cytokines. Recently, indoleamine 2,3-dioxygenase (IDO) has been identified as an enzyme endowed with powerful immunomodulatory effects, resulting from its enzymatic activity that leads to catabolism of the essential amino acid l-TRP  and . IDO is induced by IFN-γ and other pro-inflammatory cytokines in the course of an inflammatory response in many human cell types, including macrophages, astrocytes, fibroblasts, and epithelial cells. A synergistic IDO induction is seen in the presence of tumor necrosis factor-α (TNF-α), interleukin (IL)-1 or IL-6 in peripheral blood mononuclear cells, and is possibly mediated by a signaling pathway from the NF-κB and/or MAPKs. Further, certain IDO-generated, TRP-derived metabolites, in particular l-KYN, have been reported to block Ag-driven specific T-cell proliferation and even to induce T-cell death  . On the other hand, IDO has been found in various tumors of different histotypes and increments in IDO activity correlate with tumor progression  . Therefore, the activity of IDO might play an important role in the immune response regulation exerted by the antigen-presenting cells and also provide transformed cells with a potent tool to escape from the immune system assault. In this study, we investigated the expression of IDO in ATLL cells, and whether l-TRP metabolites concentrations in blood could be a useful parameter of chemotherapy efficacy for ATLL patients.
2. Materials and methods
2.1. Patient samples
Peripheral blood was drawn from 21 patients with ATLL, 11 HTLV-1 positive carriers, and 20 HTLV-1-seronegative healthy adult volunteers. The diagnosis of ATLL was based on clinical features, hematological characteristics, presence of serum antibodies to ATLL-associated antigens, and presence of HTLV-1 proviral genome in DNA from leukemic cells. Informed consent was provided according to the Declaration of Helsinki. Table 1 shows the main clinical findings of the patients with ATLL studied here.
|Age (yr), median (range)||60 (45–78)|
|WBC (×103/μL), median (range)||31.8 (0.7–233.8)|
|ATL cells (×103/μL), median (range)||27.4 (0.24–216)|
|Hb (g/dL), median (range)||12.9 (5.6–16.6)|
|Ca (mg/dL), median (range)||9.3 (5.8–11.7)|
|LDH (×102 IU/L), median (range)||11.3 (2–52.4)|
|sIL-2R (×103 U/mL)||52.7 (1.2–224)|
|CRP (mg/dL)||2.28 (0.01–10.6)|
2.2. Combination chemotherapy
Combination chemotherapy was used according to a multi-agent chemotherapy protocol, LSG15, for acute and lymphoma ATLL types. Chemotherapy consisted of two cycles of VCAP (vincristine 1 mg/m2, cyclophosphamide 350 mg/m2, doxorubicin 40 mg/m2 and prednisone 40 mg/m2), AMP (doxorubicin 30 mg/m2, ranimustine 60 mg/m2 and prednisone 40 mg/m2) and VECP (vindesine 2.4 mg/m2, etoposide 100 mg/m2, carboplatin 250 mg/m2 and prednisone 40 mg/m2). G-CSF was administered during the intervals between chemotherapy until neutrophil reconstitution was achieved.
2.3. Measurement of l-tryptophan and l-kynurenine
l-Tryptophan and l-kynurenine were measured by high-performance liquid chromatography (HPLC) with a spectrophotometric detector (TOSOH UV-8000) or fluorescence spectrometric detector (HITACHI, Tokyo, Japan) as described previously  . Briefly, separation was obtained with a reverse-phase column (Brave ODS 3 μm 150 mm × 4.6 mm; Alltech, IL, U.S.A.) and a mobile phase (flow rate 0.75 mL/min) composed of 0.1 M sodium acetate, 0.1 M acetic acid and 1% acetonitrile. The fluorescence excitation and emission wavelengths were set at 270 and 360 nm, respectively. UV signals were monitored at 355 nm for l-kynurenine.
2.4. Measurement of soluble IL-2R in serum
Soluble interleukin-2 receptor (sIL-2R) levels in the serum were measured by CELLFREE sIL-2R TEST KIT (Kyowa Medics, Japan). Briefly, the serum or various concentrations of a standard preparation of soluble IL-2R were incubated with polystyrene beads coated with the antibody to the first epitope, and with the horseradish peroxidase-conjugated antibody to the second epitope of IL-2R. The non-reactive antibodies were then washed out and orthophenylenediamine was added and allowed to react for 30 min. Sulphuric acid (1N) was added to stop the reaction, and absorption at 490 nm was measured. Soluble IL-2R is measurable up to a concentration of 6000 U/mL. Samples containing levels higher than 6000 U/mL were diluted and measured.
2.5. CD4+ cell isolation
Mononuclear cells from healthy adult volunteers, HTLV-1 positive carriers and ATLL patients were isolated by Ficoll–Paque density gradient centrifugation (Amersham Biosciences, Uppsala, Sweden) and washed with phosphate-buffered saline. CD4+ cells were isolated by positive selection from isolated mononuclear cells with directly conjugated anti-CD4 magnetic micro beads. CD4+ cells were isolated using the CD4 positive isolation kit (Dynal Biotech, Oslo, Norway).
2.6. Quantification of IDO mRNA
Total RNA was rapidly isolated using the ISOGEN RNA isolation kit (Nippon Gene, Tokyo, Japan). Total RNA (1 μg) was used for the synthesis of the first strand of cDNA. Reverse transcription (RT)-PCR was performed using the Takara mRNA selective PCR kit (Takara Biomedicals, Tokyo, Japan). The human IDO and β-actin oligonucleotide pairs were synthesized based on the following DNA sequences: IDO forward 24mer 5′-CCTGACTTATGAGAACATGGACGT-3′, IDO reverse 24mer 5′-ATACACCAGACCGTCTGATAGCTG-3′, β-actin forward 22mer 5′-GCACCACACCTTCTACAATGCG-3′, β-actin reverse 22mer 5′-ATAGCACAGCCTGGATAGCAAC-3′. The primers yielded PCR products of 324 and 196 bp, respectively. Quantification of IDO mRNA in CD4+ ATLL cells was analyzed by real-time PCR using the LightCycler System from Roche. A calibrator-normalized analysis, including an efficiency control, was performed. The PCR program included: initial denaturation (95 °C, 10 min) followed by 35 amplification cycles (95 °C, 15 s denaturation; 55 °C, 5 s annealing; 72 °C, 20 s amplification and quantification), and the melting curve (heating up to 95 °C, cool down to 69 °C, cool down to 40 °C). For quantification, expression of IDO was related to expression of the housekeeping gene β-actin, which is expressed constitutively in ATLL cells. For comparison of various LightCycler runs, a calibrator (cDNA pool) was included in each run. The LightCycler software (Version 5.32, Roche) is therefore enabled to compare various runs and to normalize expression data of the specific target marker on the housekeeping gene's expression. For efficiency correction between target and housekeeping genes we generated a ‘coefficient file’ allowing consideration of minimal efficiency variations. This coefficient file was generated by the LightCycler software from the data from a LightCycler run for the target gene and housekeeping gene with calibrator cDNA diluted 1:1, 1:10, 1:100 and 1:1000 three times each.
Smeared blood slides were fixed with 10% formalin-acetone. Each slide was boiled at 96 °C for 30 min in 1 mmol/L EDTA solution (pH 8.0) in a microwave. The slide was treated with 0.3% hydrogen peroxide to block nonspecific staining and incubated with proteinase for 15 min at room temperature. The primary antibody was mouse anti-human IDO monoclonal antibody (kindly provided by Dr. O. Takikawa) and was used at a dilution of 1:100. The slide was incubated with the antibody at 4 °C overnight. After washing in 50 mM Tris-buffered saline, a refined avidin–biotin technique in which a biotinylated secondary antibody reacts with several peroxidase-conjugated streptavidin molecules was employed for amplification using a DAKO LSAB+/HRP kit (Dako, Japan). Diaminobenzidine tetrahydrochloride (DAB) was used for the visualization of immunoreactive cells. Finally, the nuclei were counterstained with Harris hematoxylin.
Changes in serum l-TRP catabolism in ATLL patients, HTLV-positive carriers and healthy volunteers are shown in Fig. 1 . Serum l-KYN concentrations in patients with ATLL (3.32 ± 1.61 μM) were significantly higher than that in healthy adult volunteers (1.13 ± 0.32 μM) and HTLV-positive carriers (1.69 ± 0.47 μM). Serum l-TRP concentrations in patients with ATLL (40.95 ± 15.34 μM) were significantly lower than that in healthy adult volunteers (54.8 ± 14.6 μM). The ratio of l-KYN/l-TRP (K/T) in patients with ATLL (0.08 ± 0.043) was significantly higher than that in healthy adult volunteers (0.022 ± 0.009) and HTLV-positive carriers (0.035 ± 0.01). Interestingly, the serum kynurenine levels and the ratio of K/T in the acute/lymphoma ATLL types were higher than those in the chronic/smoldering ATLL types (data not shown). The level of IDO mRNA expression in CD4+ ATLL cells in patients with ATLL was significantly up-regulated compared with those in healthy adult volunteers and HTLV-positive carriers ( Fig. 2 ). The up-regulation of IDO mRNA expression was not observed in THP-1 cells. In addition, immunohistochemical results clearly demonstrated that IDO is highly expressed in cytoplasm of ATLL cells ( Fig. 3 A and B). In contrast, expression of IDO in healthy adult volunteers was not detected ( Fig. 3 C and D). Changes in serum l-KYN, l-TRP and sIL-2R concentrations, the ratio of K/T, the number of white blood cells and ATL cells in ATLL patients with chemotherapy are shown in Fig. 4 . The serum l-KYN (3.31 ± 1.44 μM vs 1.73 ± 0.74 μM; before and after chemotherapy) and sIL-2R concentrations (55.92 ± 67.63 × 103 U/mL vs 1.75 ± 1.11 × 103 U/mL) and the ratio of K/T (0.094 ± 0.052 vs 0.029 ± 0.013) and ATLL cell numbers in ATLL patients treated with chemotherapy were significantly decreased. On the contrary, the serum l-TRP concentrations (37.7 ± 8.38 μM vs 58.6 ± 9.32 μM) significantly increased. Interestingly, the serum l-TRP concentrations increased only during the chemotherapy. The serum l-KYN and sIL-2R concentrations and the ratio of K/T in ATLL patients without chemotherapy were constant at a high level, but serum l-TRP concentrations remained at a low level (data not shown).
In this study, we demonstrated that highly enhanced IDO expression in ATLL cells significantly accelerated l-TRP catabolism resulting in low l-TRP and high l-KYN concentrations in serum. In addition, our present study demonstrated changes in IDO-initiating l-TRP catabolism in blood with chemotherapy for ATLL patients. It has been reported that increased l-KYN, neopterin and decreased l-TRP concentrations in serum are first observed in HTLV-1 seronegative, asymptomatic seropositive carrier, HAM/TSP and primary ATLL patients and that high blood l-KYN concentrations could be one factor of poor prognosis for ATLL  . Indeed, our present results showed that the increase in serum l-KYN levels and reduction in serum l-TRP levels caused by the highly expression of IDO in ATL cells paralleled with disease activity. Thus, serum kynurenine levels and the ratio of K/T may be useful for the evaluation of ATLL status. However, the exact mechanisms of increased l-TRP metabolism in ATLL patients are still unclear. When we examined the expression of IDO at protein and mRNA levels in human ATLL cells, expression of IDO was significantly increased in all ATLL cases analyzed. Further, this study clearly demonstrates that IDO is strongly expressed in cytoplasm in ATLL cells. It is known that IDO is induced by several different cytokines: up-regulated by IL-1, IL-6, and TNF-α, and down-regulated by IL-4 and TGF-β through interferon-γ-dependent and/or -independent mechanisms in many cell types  ; and that its expression is enhanced synergistically by those pro-inflammatory cytokines in certain circumstances , , , , and . This synergistic expression is regulated at the level of transcription and/or synergistic up-regulation of IDO expression in response to INF-γ, TNF-α, IL-1, IL-6 and IL-10, which are dependent upon activation of the transcription factors STAT-1, IRF-1 and NF-κB , , , and . ATLL cells are also known to associate with the constitutive activation of JAK/STAT proteins  , and with NF-κB in primary ATLL cells  and . These observations further support that high IDO expression was determined both at protein and mRNA levels in human ATLL cells. Indeed, recent clinical studies have established that inhibition of the NF-κB signaling pathway is a potential strategy for the treatment of ATLL  .
In the present study, we first report in the literature that l-TRP levels increased with the reduction of ATLL cells after chemotherapy in ATLL patients, and that l-KYN levels and the ratio of K/T correlated with sIL-2R levels. These findings suggest that l-TRP catabolism is increased in ATLL cells, possibly with elevation of various inducers of IDO including pro-inflammatory cytokines. In fact, it has been reported that IL-1β, IL-2, TNF-α and IFN-γ are produced in ATLL cells  . Furthermore, it is well known that sIL-2R levels are useful as an indicator of ATLL progression status and prognosis for survival  . l-TRP catabolites and the ratio of K/T were also specific in addition to sIL-2R as an indicator of chemotherapy. However, the pathological and functional significance of the increased l-TRP catabolism in ATLL cells has not been determined. IDO plays a key role in an immunosuppressive mechanism shared by several different immune cell types. We speculate that inhibition of IDO in ATLL patients may be useful chemotherapy, because it has been recently reported that inhibition of IDO, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy  . In fact, two major theories of l-TRP catabolism recently have been proposed to account for tolerance induction via l-TRP catabolism. One theory assumes that downstream metabolites of l-TRP, collectively known as l-KYN, act to suppress immune reactivity, probably through direct interactions with effector T lymphocytes and other cell types. The other theory posits that l-TRP itself plays a key role and breakdown of this molecule suppresses T-cell proliferation by critically reducing the availability of this indispensable amino acid under local tissue microenvironments. Indeed, IDO expression within the tumoral environment, irrespective of the producing cell, could result in evasion of immune-mediated rejection of tumor cells. In non-small cell lung adenocarcinoma, tumor in filtrating eosinophils appear to be solely responsible for the occurrence of an IDO-dependent immunosuppression. It was also observed that tumor progression was accelerated in patients displaying a large amount of these cells in the inflammatory infiltrate  . Together with the finding that HLA-G molecules and IDO can be co-expressed and both can be induced as a response to pro-inflammatory molecules  and , it becomes apparent than this can be utilized as an added mechanism to mediate tumor immune escape from T-cell recognition and destruction. On the other hand, it has been reported that IDO was found to play an important role in compromising anti-tumor immunity by regulating cytotoxic activity of NK cells  and . These difference roles of between in tumor cells and in NK cells may be explains from the aspect of immunological homeostasis. IDO derived from tumor cells appear to play an essential role in the down-regulation of host immune responses. IDO in NK cells appear to maintain the normal cytotoxicity against tumor cells. Both immune tolerance and rejection of tumor cells must be normal behaviors of the biological immune system. We speculate that highly expressed IDO in ATLL cells might enable them to initially avoid immune attack against Tax, which is a clinical viral protein for T-cell immortalization and the most popular target for HTLV-1-specific CTL  , and then to reduce T-cell priming and the invasion of effector T-cells via local l-TRP depletion. Because it is recently reported that inhibition of IDO block host-mediated immunosuppression and enhance anti-tumor immunity in the setting of combined chemo-immunotherapy regimens  and , further study will require elicitation of the characteristics of IDO-positive ATLL cells, and inhibition of IDO in target cells may be a useful tool for drug resistant ATLL.
In conclusion, we directly demonstrated that IDO is obviously expressed in human ATLL cells, and that IDO-initiating l-TRP catabolism changes with chemotherapy.
Conflict of interest statement
We appreciate the assistance of Minako Hoshi. We also thank John Cole for proofreading the English of this manuscript.
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a Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
b Gifu Municipal Hospital, Gifu, Japan
c Ichinomiya Municipal Kisogawa Hospital, Ichinomiya, Japan
d Human Health Sciences Graduate School of Medicine and Faculty of Medicine Kyoto University, Kyoto, Japan
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