Indoleamine 2,3-dioxygenase as a new target for malignant glioma therapy

2009 ◽  
Vol 111 (2) ◽  
pp. 230-237 ◽  
Author(s):  
Takeshi Miyazaki ◽  
Kouzo Moritake ◽  
Kazuo Yamada ◽  
Nobumasa Hara ◽  
Harumi Osago ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Anticancer Drugs ◽  
Malignant Tumors ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
Interferon Γ ◽  
Therapeutic Effects ◽  
Indoleamine 2,3 Dioxygenase ◽  
Immune Resistance ◽  
Ifn Γ

Object Indoleamine 2,3-dioxygenase (IDO), a kynurenine pathway (KP) enzyme catalyzing oxidation of the essential amino acid tryptophan (Trp), is thought to be involved in the immune resistance of malignant tumors through T-cell inactivation caused by Trp depletion and metabolite accumulation. Human malignant gliomas may use this strategy to escape immune attack. The object of this study was to investigate the possibility of IDO-dependent Trp depletion by malignant gliomas and the practicability of using an IDO inhibitor together with anticancer drugs to reserve Trp without decreasing the cytotoxicity of the drugs. Methods The authors studied expression of IDO and other KP enzymes and the effects of an IDO inhibitor, 1-methyl L-tryptophan (1MT), on Trp metabolism and cytotoxicity of anticancer drugs, together with direct measurement of KP metabolites, in cultured human malignant glioma cells. Results Upon interferon-γ (IFN-γ) stimulation, the glioma cells greatly increased their IDO mRNA expression concomitant with depletion of Trp. The IDO inhibitor 1MT successfully prevented Trp consumption by the stimulated glioma cells. Combining 1MT with anticancer drugs (temozolomide, bischloroethylnitrosourea [BCNU], etoposide and cisplatin) did not interfere with the drugs' suppression of growth of LN229 glioma cells but rather increased their inhibitory effects on IDO activity. Conclusions These findings suggest that the robust IDO expression with rapid consumption of Trp in human glioma cells induced by IFN-γ could lead to immune resistance in glioma cells. Indoleamine 2,3-dioxygenase inhibitors that prevent Trp depletion could be used with anticancer drugs to improve therapeutic effects.

Soluble CD70: a novel immunotherapeutic agent for experimental glioblastoma

2010 ◽  
Vol 113 (2) ◽  
pp. 280-285 ◽  
Author(s):  
James Miller ◽  
Guenter Eisele ◽  
Ghazaleh Tabatabai ◽  
Steffen Aulwurm ◽  
Gabriele von Kürthy ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Malignant Gliomas ◽  
Ectopic Expression ◽  
Glioma Cells ◽  
Interferon Γ ◽  
Soluble Form ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells

Object Given the overall poor outcome with current treatment strategies in malignant gliomas, immunotherapy has been considered a promising experimental approach to glioblastoma for more than 2 decades. A cell surface molecule, CD70, may induce potent antitumor immune responses via activation of the costimulatory receptor CD27 expressed on immune effector cells. There is evidence that a soluble form of CD70 (sCD70) may exhibit biological activity, too. A soluble costimulatory ligand is attractive because it may facilitate immune activation and may achieve a superior tissue distribution. Methods To test the antiglioma effect of sCD70, the authors genetically modified SMA-560 mouse glioma cells to secrete the extracellular domain of CD70. They assessed the immunogenicity of the transfected cells in cocultures with immune effector cells by the determination of immune cell proliferation and the release of interferon-γ. Syngeneic VM/Dk mice were implanted orthotopically with control or sCD70-releasing glioma cells to determine a survival benefit mediated by sCD70. Depletion studies were performed to identify the cellular mediators of prolonged survival of sCD70-releasing glioma-bearing mice. Results The authors found that ectopic expression of sCD70 enhanced the proliferation and interferon-γ release of syngeneic splenocytes in vitro. More importantly, sCD70 prolonged the survival of syngeneic VM/Dk mice bearing intracranial SMA-560 gliomas. The survival rate at 60 days increased from 5 to 45%. Antibody-mediated depletion of CD8-positive T cells abrogates the survival advantage conferred by sCD70. Conclusions These data suggest that sCD70 is a potent stimulator of antiglioma immune responses that depend critically on CD8-positive T cells. Soluble CD70 could be a powerful adjuvant for future immunotherapy trials for glioblastoma.

Prolonged survival of mice with glioma injected intracerebrally with double cytokine—secreting cells

1995 ◽  
Vol 83 (6) ◽  
pp. 1038-1044 ◽  
Author(s):  
Terry Lichtor ◽  
Roberta P. Glick ◽  
Tae Sung Kim ◽  
Roger Hand ◽  
Edward P. Cohen
Keyword(s):  
Cell Line ◽  
Interleukin 2 ◽  
Glioma Cells ◽  
Fibroblast Cell ◽  
Interferon Γ ◽  
Glioma Cell Line ◽  
Mouse Fibroblast ◽  
Spleen Cells ◽  
Content Type ◽  
Ifn Γ

✓ A novel approach toward the treatment of glioma was developed in a murine model. The genes for both interleukin-2 (IL-2) and interferon-γ (IFN-γ) were first transfected into a mouse fibroblast cell line that expresses defined major histocompatibility complex (MHC) determinants (H—2k). The double cytokine—secreting cells were then cotransplanted intracerebrally with the Gl261 murine glioma cell line into syngeneic C57BL/6 mice (H—2b) whose cells differed at the MHC from the cellular immunogen. The results indicate that the survival of mice with glioma injected with the cytokine-secreting allogeneic cells was significantly prolonged, relative to the survival of mice receiving equivalent numbers of glioma cells alone. Using a standard 51Cr-release assay, the specific release of isotope from labeled Gl261 cells coincubated with spleen cells from mice injected intracerebrally with the glioma cells and the cytokine-secreting fibroblasts was significantly higher than the release of isotope from glioma cells coincubated with spleen cells from nonimmunized mice. The cellular antiglioma response was mediated by natural killer/lymphokine-activated killer and Lyt-2.2+ (CD8+) cells. The increased survival of mice with glioma and the specific immunocytotoxic responses after immunization with fibroblasts modified to secrete both IL-2 and IFN-γ indicate the potential of an immunotherapeutic approach to gliomas with cytokine-secreting cells.

scholarly journals Checks and balances between human cytomegalovirus replication and indoleamine-2,3-dioxygenase

2014 ◽  
Vol 95 (3) ◽  
pp. 659-670 ◽  
Author(s):  
Albert Zimmermann ◽  
Sebastian Hauka ◽  
Marco Maywald ◽  
Vu Thuy Khanh Le ◽  
Silvia K. Schmidt ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Human Cytomegalovirus ◽  
Cell Types ◽  
Interferon Γ ◽  
Counter Measures ◽  
Indoleamine 2,3 Dioxygenase ◽  
Infected Cells ◽  
Hcmv Replication ◽  
Ifn Γ ◽  
The Impact

Despite a rigorous blockade of interferon-γ (IFN-γ) signalling in infected fibroblasts as a mechanism of immune evasion by human cytomegalovirus (HCMV), IFN-γ induced indoleamine-2,3-dioxygenase (IDO) has been proposed to represent the major antiviral restriction factor limiting HCMV replication in epithelial cells. Here we show that HCMV efficiently blocks transcription of IFN-γ-induced IDO mRNA both in infected fibroblasts and epithelial cells even in the presence of a preexisting IFN-induced antiviral state. This interference results in severe suppression of IDO bioactivity in HCMV-infected cells and restoration of vigorous HCMV replication. Depletion of IDO expression nonetheless substantially alleviated the antiviral impact of IFN-γ treatment in both cell types. These findings highlight the effectiveness of this IFN-γ induced effector gene in restricting HCMV productivity, but also the impact of viral counter-measures.

scholarly journals Preliminary Report: Rapid Intraoperative Detection of Residual Glioma Cell in Resection Cavity Walls Using a Compact Fluorescence Microscope

2021 ◽  
Vol 10 (22) ◽  
pp. 5375
Author(s):  
Jiro Akimoto ◽  
Shinjiro Fukami ◽  
Megumi Ichikawa ◽  
Kenta Nagai ◽  
Michihiro Kohno
Keyword(s):  
Tumor Cell ◽  
Malignant Glioma ◽  
Tumor Cells ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
Fluorescence Microscope ◽  
Talaporfin Sodium ◽  
Surgical Microscope ◽  
Resection Cavity ◽  
Intraoperative Detection

Objective: The surgical eradication of malignant glioma cells is theoretically impossible. Therefore, reducing the number of remaining tumor cells around the brain–tumor interface (BTI) is crucial for achieving satisfactory clinical results. The usefulness of fluorescence–guided resection for the treatment of malignant glioma was recently reported, but the detection of infiltrating tumor cells in the BTI using a surgical microscope is not realistic. Therefore, we have developed an intraoperative rapid fluorescence cytology system, and exploratorily evaluated its clinical feasibility for the management of malignant glioma. Materials and methods: A total of 25 selected patients with malignant glioma (newly diagnosed: 17; recurrent: 8) underwent surgical resection under photodiagnosis using photosensitizer Talaporfin sodium and a semiconductor laser. Intraoperatively, a crush smear preparation was made from a tiny amount of tumor tissue, and the fluorescence emitted upon 620/660 nm excitation was evaluated rapidly using a compact fluorescence microscope in the operating theater. Results: Fluorescence intensities of tumor tissues measured using a surgical microscope correlated with the tumor cell densities of tissues evaluated by measuring the red fluorescence emitted from the cytoplasm of tumor cells using a fluorescence microscope. A “weak fluorescence” indicated a reduction in the tumor cell density, whereas “no fluorescence” did not indicate the complete eradication of the tumor cells, but indicated that few tumor cells were emitting fluorescence. Conclusion: The rapid intraoperative detection of fluorescence from glioma cells using a compact fluorescence microscope was probably useful to evaluate the presence of tumor cells in the resection cavity walls, and could provide surgical implications for the more complete resection of malignant gliomas.

scholarly journals Inhibition of Cyclin D1 Expression in Human Glioblastoma Cells is Associated with Increased Temozolomide Chemosensitivity

2018 ◽  
Vol 51 (6) ◽  
pp. 2496-2508 ◽  
Author(s):  
Danfeng Zhang ◽  
Dawei Dai ◽  
Mengxia Zhou ◽  
Zhenxing Li ◽  
Chunhui Wang ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Cyclin D1 ◽  
Cell Lines ◽  
Effective Means ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
Normal Brain ◽  
Induced Apoptosis

Background/Aims: Cyclin D1 (CCND1) is frequently overexpressed in malignant gliomas. We have previously shown ectopic overexpression of CCND1 in human malignant gliomas cell lines. Methods: Quantitative reverse transcriptase PCR (qRT-PCR) and Western Blot (WB) was performed to investigate the expression of CCND1 in glioma tissues and cell lines. The biological function of CCND1 was also investigated through knockdown and overexpression of BCYRN1 in vitro. Results: Here we reported that CCND1 expression was positively associated with the pathological grade and proliferative activity of astrocytomas, as the lowest expression was found in normal brain tissue (N = 3) whereas the highest expression was in high-grade glioma tissue (N = 25). Additionally, we found that the expression level of CCND1 was associated with IC50 values in malignant glioma cell lines. Forced inhibition of CCND1 increased temozolomide efficacy in U251 and SHG-44 cells. After CCND1 overexpression, the temozolomide efficacy decreased in U251 and SHG-44 cells. Colony survival assay and apoptosis analysis confirmed that CCND1 inhibition renders cells more sensitive to temozolomide treatment and temozolomide-induced apoptosis in U251 and SHG-44 cells. Inhibition of P-gp (MDR1) by Tariquidar overcomes the effects of CCND1 overexpression on inhibiting temozolomide-induced apoptosis. Inhibition of CCND1 inhibited cell growth in vitro and in vivo significantly more effectively after temozolomide treatments than single temozolomide treatments. Finally, inhibition of CCND1 in glioma cells reduced tumor volume in a murine model. Conclusion: Taken together, these data indicate that CCND1 overexpression upregulate P-gp and induces chemoresistance in human malignant gliomas cells and that inhibition of CCND1 may be an effective means of overcoming CCND1 associated chemoresistance in human malignant glioma cells.

Targeting adenovirus to CD80 and CD86 receptors increases gene transfer efficiency to malignant glioma cells

2007 ◽  
Vol 107 (3) ◽  
pp. 617-627 ◽  
Author(s):  
Ilya V. Ulasov ◽  
Angel A. Rivera ◽  
Yu Han ◽  
David T. Curiel ◽  
Zeng B. Zhu ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Brain Tumors ◽  
Malignant Glioma ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
Luciferase Reporter ◽  
Transduction Efficiency ◽  
Wild Type ◽  
Malignant Glioma Cells

Object Gene therapy protocols for malignant gliomas utilize adenoviral vectors that rely almost exclusively on the adenovirus serotype 5 (Ad5) backbone. The authors have previously shown that chimeric vectors that bind to the Ad3 receptor, or CD46, increase the transduction efficiency of malignant brain tumors. In light of the debate regarding the efficacy of CD46 compared with CD80/CD86 in binding Ad3 virions, the authors now examine the expression and transduction efficiency of Ad5/3 chimeras that bind via CD80/CD86. Methods The authors first analyzed CD80/CD86 expression in glioma cell lines. They then used three replication-defective vectors containing a luciferase reporter gene: Ad5/3 (containing the tail and shaft domain of Ad5 and the knob domain of Ad3); Ad3/5 (containing the tail of Ad5, shaft of Ad3, and knob of Ad5); and Ad3/3 (containing the tail of Ad5, shaft of Ad3, and knob of Ad3). These vectors were analyzed both in vitro and in vivo against malignant glioma cells. To examine further the effect of Ad5/3 fiber modification, the authors created an oncolytic vector, conditionally replicative Ad5/3 (CRAd5/3). Results The Ad5/3 vector showed a 10- to 100-fold enhanced transduction efficiency of malignant glioma compared with replication-defective wild-type adenovirus (reAd5) (p < 0.05). Moreover the use of Ad5/3 reduced transgene expression by more than 90% in normal human brain cells compared with reAd5. Finally, the use of CRAd5/3 inhibited tumor cell proliferation by 43% more than replication-competent wild-type virus in vitro (p < 0.05). Conclusions The results of this study demonstrate that the Ad5/3 vector offers superior transduction efficiency and low toxicity in the setting of brain tumors, and therefore represents a potential new approach to gene therapy for malignant gliomas.

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

Neurosurgery ◽  
2013 ◽  
Vol 72 (6) ◽  
pp. 1031-1039 ◽  
Author(s):  
Kentaro Mitsuka ◽  
Tomoyuki Kawataki ◽  
Eiji Satoh ◽  
Takayuki Asahara ◽  
Toru Horikoshi ◽  
...  
Keyword(s):  
Immune Escape ◽  
Malignant Tumors ◽  
Histological Grade ◽  
Malignant Gliomas ◽  
Survival Rates ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Tumor Immune Escape ◽  
Secondary Glioblastoma ◽  
Indoleamine 2,3 Dioxygenase

Abstract BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is a tryptophan catabolic enzyme involved in immune tolerance and tumor immune escape processes. Recently, IDO expression has been found to correlate with the prognosis of malignant tumors, but the implication of IDO in glioma progression remains unknown. OBJECTIVE: To investigate the relationship between IDO expression and histological malignancy in gliomas. METHODS: IDO expression was examined in a total of 75 surgical specimens obtained from 68 patients with glioma using immunohistochemical staining. The 75 specimens included 15 diffuse astrocytomas, 21 anaplastic astrocytomas, and 39 glioblastomas. Six of 39 glioblastomas were secondary glioblastomas, transforming from grade II or III gliomas that had been determined at the first surgery. IDO expression rate was compared in each histological grade, and patient survival was analyzed. RESULTS: Expression of IDO was found in 72 of 75 gliomas at varying intensities. Stronger expression of IDO was more likely to be observed in malignant gliomas compared with low-grade gliomas. IDO expression in the 6 cases of secondary glioblastoma was stronger than in the initial low-grade glioma. Survival analysis using the Kaplan-Meier method revealed that grade IV patients with strong IDO expression had significantly worse overall survival rates (P = .04) than patients with weak IDO expression. CONCLUSION: 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.

scholarly journals Interferon-γ enhances the therapeutic effect of mesenchymal stem cells on experimental renal fibrosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ryo Kanai ◽  
Ayumu Nakashima ◽  
Shigehiro Doi ◽  
Tomoe Kimura ◽  
Ken Yoshida ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Prostaglandin E2 ◽  
Conditioned Medium ◽  
Renal Fibrosis ◽  
Interferon Γ ◽  
Prostaglandin E ◽  
Therapeutic Effects ◽  
Control Mscs ◽  
Ifn Γ

AbstractMesenchymal stem cells (MSCs) administered for therapeutic purposes can be activated by interferon-γ (IFN-γ) secreted from natural killer cells in injured tissues and exert anti-inflammatory effects. These processes require a substantial period of time, leading to a delayed onset of MSCs’ therapeutic effects. In this study, we investigated whether pretreatment with IFN-γ could potentiate the anti-fibrotic ability of MSCs in rats with ischemia–reperfusion injury (IRI) and unilateral ureter obstruction. Administration of MSCs treated with IFN-γ strongly reduced infiltration of inflammatory cells and ameliorated interstitial fibrosis compared with control MSCs without IFN-γ treatment. In addition, conditioned medium obtained from IFN-γ-treated MSCs decreased fibrotic changes in cultured cells induced by transforming growth factor-β1 more efficiently than that from control MSCs. Most notably, secretion of prostaglandin E2 from MSCs was significantly increased by treatment with IFN-γ. Increased prostaglandin E2 in conditioned medium obtained from IFN-γ-treated MSCs induced polarization of immunosuppressive CD163 and CD206-positive macrophages. In addition, knockdown of prostaglandin E synthase weakened the anti-fibrotic effects of MSCs treated with IFN-γ in IRI rats, suggesting the involvement of prostaglandin E2 in the beneficial effects of IFN-γ. Administration of MSCs treated with IFN-γ might represent a promising therapy to prevent the progression of renal fibrosis.

scholarly journals ACT-15 AD-SGE-REIC GENE THERAPY FOR MALIGNANT GLIOMA

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii14-ii14
Author(s):  
Kazuhiko Kurozumi ◽  
Kentarou Fujii ◽  
Yosuke Shimazu ◽  
Yusuke Tomita ◽  
Yuji Matsumoto ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Malignant Glioma ◽  
Adenoviral Vector ◽  
Human Cancer ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
Dependent Manner ◽  
Recurrent Malignant Glioma ◽  
Malignant Glioma Cells

Abstract INTRODUCTION Malignant gliomas are one of the most common and aggressive intracranial neoplasms in humans. Expression of the gene encoding reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) is reduced in a variety of human cancer cells. We previously showed the antitumor effect of an adenoviral vector carrying REIC/Dkk-3 gene (Ad-CAG-REIC). Recently, we have also developed a novel adenoviral vector expressing REIC/Dkk-3 (Ad-SGE-REIC). We assessed the anti-glioma effect of the Ad-SGE-REIC and planned a clinical trial of Ad-SGE-REIC for malignant glioma. MATERIALS AND METHODS We evaluated a cytotoxicity assay to treatments with Ad-SGE-REIC, Ad-CAG-REIC, or Ad-LacZ (control) using malignant glioma cells. The survival of mice in each group was analyzed by the Kaplan-Meier method. We also performed Good Laboratory Practice (GLP) toxicology tests and prepared a protocol for this clinical trial. RESULTS The treatment with Ad-SGE-REIC showed the number of malignant glioma cells attached to the bottom of culture wells was significantly reduced in a time-dependent manner. Mice treated with Ad-SGE-REIC significantly prolonged survival time more than those treated with other vectors. A cGMP product of Ad-SGE-REIC was developed and supplied by a startup biotech company, Momotaro-Gene Inc. We conducted GLP toxicology tests using the intracranial injection of higher doses of Ad-SGE-REIC at Shin Nippon Biomedical Laboratories (SNBL Japan). After finishing the consultation with Pharmaceuticals and Medical Devices Agency (PMDA), we prepared a protocol for a phase I/IIa clinical trial of Ad-SGE-REIC for the treatment of recurrent malignant glioma with our academic research organization (ARO), supported by Japan Agency for Medical Research and Development (AMED). This protocol was reviewed by our institution review board in March 2019. We submitted a notification of this trial in April 2019. CONCLUSIONS We demonstrated the anti-glioma effect of Ad-SGE-REIC. We start a phase I/IIa clinical trial of Ad-SGE-REIC for the treatment of recurrent malignant glioma (https://jrct.niph.go.jp/en-latest-detail/jRCT2063190013).

Sign in / Sign up

Export Citation Format

Share Document