Expression of Indoleamine 2,3-Dioxygenase and Correlation With Pathological Malignancy in Gliomas

Mitsuka, Kentaro; Kawataki, Tomoyuki; Satoh, Eiji; Asahara, Takayuki; Horikoshi, Toru; Kinouchi, Hiroyuki

doi:10.1227/neu.0b013e31828cf945

Cited by 90 publications

(64 citation statements)

References 37 publications

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“…As noted, GBM tumors secrete high levels of iDo (119,121). GBMs express significantly higher iDo levels than do lowgrade gliomas, and iDo expression negatively correlates with survival (199,200). Wainright et al injected iDo-deficient and iDo-competent glioma cells into the cerebral hemispheres of mice, and demonstrated that the mice with iDo-deficient glioma cells survived far longer.…”

Section: Inhibitors Of the Kynurenine Pathwaymentioning

confidence: 98%

The Kynurenine Pathway: A Primary Resistance Mechanism in Patients with Glioblastoma

Sordillo

Helson

2017

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Section: Inhibitors Of the Kynurenine Pathwaymentioning

confidence: 98%

The Kynurenine Pathway: A Primary Resistance Mechanism in Patients with Glioblastoma

Sordillo

Helson

2017

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“…8 In glioma, we have reported that IDO was highly expressed in human glioblastoma tissue as compared with low-grade glioma, and IDO expression was increased in secondary glioblastoma tissue with malignant transformation. 13 Therefore, IDO could be a novel and reliable prognostic indicator of patient outcomes and may be a crucial therapeutic target for malignant glioma.…”

Section: Discussionmentioning

confidence: 99%

“…[3][4][5][6][7][10][11][12]15,25 We have already reported that IDO is highly expressed in human glioblastoma tissue compared with low-grade glioma and that IDO expression is increased in the secondary glioblastoma tissue with malignant transformation. 13 In addition, a recent study showed that serum Trp levels were significantly decreased in patients with glioblastoma compared with healthy controls. 18 These findings suggest that Trp catabolism is definitely associated with glioma progression, and IDO inhibition seems to be a promising target for cancer treatment.…”

mentioning

confidence: 99%

Synergistic antitumor effect with indoleamine 2,3-dioxygenase inhibition and temozolomide in a murine glioma model

Hanihara¹,

Kawataki²,

Oh-oka

et al. 2016

JNS

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M alignant glioma is the most common brain tumor in adults; it has an aggressive lethal nature and a median survival of only 14 months, despite the standard established therapy of maximum resection followed by radiation and chemotherapy. Several immunotherapies, such as dendritic cell therapy, have been evaluated as new adjuvant approaches. However, the efficacy of immunotherapy for patients with malignant glioma is limited for several reasons, including the anatomical isolation of the central nervous system by the blood-brain barrier, the absence of a lymphatic drainage system, and the ability of glioma cells to escape recognition by the immune system. Recent studies suggest that indoleamine 2,3-dioxygenase (IDO), the initial rate-limiting enzyme in tryptophan (Trp) metabolism, may be involved in such tumor-induced escape from immunosurveillance, showing an immunosuppressive function.14,27 IDO is expressed in various human cancers such as malignant melanoma, ovarabbreviatioNs FACS = fluorescence-activated cell sorter; GAPDH = glyceraldehyde-3-phosphate dehydrogenase; IDO = indoleamine 2,3-dioxygenase; IDO-KD = IDO-knockdown; INF-g = interferon-g; PBS = phosphate-buffered saline; RT-PCR = real-time polymerase chain reaction; SEM = standard error of the mean; shRNA = short hairpin RNA; TMZ = temozolomide; Treg = regulatory T cell; Trp = tryptophan; 1-MT = 1-methyl-l-tryptophan. Thus, IDO may be a therapeutic target for malignant cancer. The authors have recently shown that IDO expression is markedly increased in human glioblastoma and secondary glioblastoma with malignant change, suggesting that IDO targeting may also have therapeutic potential for patients with glioma. The aim of this study was to investigate the antitumor effect of IDO inhibition and to examine the synergistic function of IDO inhibitor and temozolomide (TMZ) in a murine glioma model. methods Murine glioma GL261 cells and human glioma U87 cells were included in this study. The authors used 3 mouse models to study glioma cell growth: 1) a subcutaneous ectopic model, 2) a syngeneic intracranial orthotopic model, and 3) an allogenic intracranial orthotopic model. IDO inhibition was achieved via knockdown of IDO in GL261 cells using short hairpin RNA (shRNA) and through oral administration of the IDO inhibitor, 1-methyl-l-tryptophan (1-MT). Tumor volume in the subcutaneous model and survival time in the intracranial model were evaluated. results In the subcutaneous model, oral administration of 1-MT significantly suppressed tumor growth, and synergistic antitumor effects of 1-MT and TMZ were observed (p < 0.01). Mice containing intracranially inoculated IDO knockdown cells had a significantly longer survival period as compared with control mice (p < 0.01). coNclusioNs These results suggest that IDO expression is implicated in immunosuppression and tumor progression in glioma cells. Therefore, combining IDO inhibition with standard TMZ treatment could be an encouraging therapeutic strategy for patients with malignant glioma.

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“…Within CNS tumors, engrafted TAMs overwhelmingly demonstrate the M2 phenotype [39]. Furthermore, the presence of M2 type TAMs appears to correlate with tumor grade.…”

Section: Tumor Associated Macrophagesmentioning

confidence: 98%

“…Interestingly, the authors further demonstrated that tumor-cell specific expression of IDO, rather than peripheral expression of this enzyme is critical for maintaining this immunosuppressive state [38]. IDO might have a clinical and translational therapeutic potential, as its expression correlates with tumor grade and has a negative impact on overall survival for patients with gliomas [39]. Ongoing efforts to functionally characterize CNS tumor cells continue to implicate cell-cell and cell secreted mediator interactions in addition to those discussed above.…”

Section: Cns Tumor Cellsmentioning

confidence: 99%

Immunopathology of Central Nervous System Tumors

Showers

Sonabend²,

Anderson³

2014

Immunome Res

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The central nervous system (CNS) is characterized by unique immune biology. Distinct mechanisms of CNS immune surveillance and activation have important implications in tumor development as CNS tumors are known to evade anti-tumoral immunity, and may also contribute to immunosuppression. Multiple cell-surface and secreted mediators, expressed in both CNS tumor cells and responding immune cells, have been shown to influence the immune response to CNS tumors. In this review we provide an overview of CNS tumor immune escape and immunosuppression, highlighting the cellular and molecular features associated with both CNS tumors cells and responding immune cells. In this context, we discuss of the role of the M1 and M2 tumor associated macrophage phenotypes, myeloid derived suppressor cells, regulatory T-cells, as well as many immunomodulatory cytokines. Additionally, recent insights into the STAT-3 intracellular signaling pathway and the presence of active human CMV infection in the context of CNS tumor development are discussed.

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Expression of Indoleamine 2,3-Dioxygenase and Correlation With Pathological Malignancy in Gliomas

Abstract: : IDO is expressed more strongly in both primary and secondary glioblastoma tissue than low-grade glioma and may affect clinical outcome. If IDO promotes glioma cells to escape from the immune system, IDO may be a crucial therapeutic target for malignant gliomas.

Cited by 90 publications

References 37 publications

The Kynurenine Pathway: A Primary Resistance Mechanism in Patients with Glioblastoma

The Kynurenine Pathway: A Primary Resistance Mechanism in Patients with Glioblastoma

Synergistic antitumor effect with indoleamine 2,3-dioxygenase inhibition and temozolomide in a murine glioma model

Immunopathology of Central Nervous System Tumors

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