Immunotherapy of Diffuse Gliomas: Biological Background, Current Status and Future Developments

Löhr, Mario; Molcanyi, Marek; Poggenborg, Jörg; Spuentrup, Elmar; Runge, Matthias; Röhn, Gabriele; Härtig, Wolfgang; Hescheler, Jürgen; Hampl, Jürgen A.

doi:10.1111/j.1750-3639.2009.00315.x

Cited by 2,988 publications

(60 citation statements)

References 287 publications

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“…That immunotherapy can be efficient and safe was shown by a number of clinical trials aiming at a specific antiglioma T-cell activation. These approaches include adoptive transfer of tumor-reactive T cells, ex vivo tumor antigen-primed dendritic cells, or vaccination with peptides, inactivated autologous tumor cells and genemodified tumor cells (4). However, despite beneficial observations patients were not cured and some of them even did not respond to antiglioma immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Effector T-Cell Infiltration Positively Impacts Survival of Glioblastoma Patients and Is Impaired by Tumor-Derived TGF-β

Lohr

Ratliff

Huppertz

et al. 2011

Clinical Cancer Research

298

251

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Purpose: In glioma-in contrast to various other cancers-the impact of T-lymphocytes on clinical outcome is not clear. We investigated the clinical relevance and regulation of T-cell infiltration in glioma.Experimental Design: T-cell subpopulations from entire sections of 93 WHO II-IV gliomas were computationally identified using markers CD3, CD8, and Foxp3; survival analysis was then done on primary glioblastomas (pGBM). Endothelial cells expressing cellular adhesion molecules (CAM) were similarly computationally quantified from the same glioma tissues. Influence of prominent cytokines (as measured by ELISA from 53 WHO II-IV glioma lysates) on CAM-expression in GBM-isolated endothelial cells was determined using flow cytometry. The functional relevance of the cytokine-mediated CAM regulation was tested in a transmigration assay using GBM-derived endothelial cells and autologous T-cells.Results: Infiltration of all T-cell subsets increased in high-grade tumors. Most strikingly, within pGBM, elevated numbers of intratumoral effector T cells (T eff , cytotoxic and helper) significantly correlated with a better survival; regulatory T cells were infrequently present and not associated with GBM patient outcome. Interestingly, increased infiltration of T eff cells was related to the expression of ICAM-1 on the vessel surface. Transmigration of autologous T cells in vitro was markedly reduced in the presence of CAM-blocking antibodies. We found that TGF-b molecules impeded transmigration and downregulated CAM-expression on GBM-isolated endothelial cells; blocking TGF-b receptor signaling increased transmigration.Conclusions: This study provides comprehensive and novel insights into occurrence and regulation of T-cell infiltration in glioma. Specifically, targeting TGF-b1 and TGF-b2 might improve intratumoral T-cell infiltration and thus enhance effectiveness of immunotherapeutic approaches. Clin Cancer Res; 17(13); 4296-308. Ó2011 AACR.

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Section: Introductionmentioning

confidence: 99%

Effector T-Cell Infiltration Positively Impacts Survival of Glioblastoma Patients and Is Impaired by Tumor-Derived TGF-β

Lohr

Ratliff

Huppertz

et al. 2011

Clinical Cancer Research

298

251

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“…Despite the use of aggressive surgery in combination with chemotherapy, biological therapy and radiotherapy, gliomas continue to be therapeutically challenging (2). For patients with glioblastoma, the relative 5-year survival rate is <5% (3).…”

Section: Introductionmentioning

confidence: 99%

Suppression of PDCD4 mediated by the long non-coding RNA HOTAIR inhibits the proliferation and invasion of glioma cells

Chen¹,

Bian²,

Zhao³

et al. 2016

Oncology Letters

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Abstract. Programmed cell death protein 4 (PDCD4) has recently been demonstrated to be implicated in translation and transcription, and the regulation of cell growth. However, the mechanisms underlying PDCD4 function in glioma cells remain to be elucidated. The current study investigated the function and regulation of PDCD4 and the results demonstrated that the expression of PDCD4 was significantly reduced in glioma cells compared with normal cells. When PDCD4 was overexpressed in glioma cells, the proliferation rate and invasive capability of the cells greatly decreased, suggesting that PDCD4 functions as a tumor suppressor in this cell type. In addition, the histone modification status of the PDCD4 gene was analyzed, and chromatin immunoprecipitation assay identified a high density of histone 3 lysine 27 trimethylation on the promoter of PDCD4, which was associated with the long non-coding RNA, homeobox transcript antisense RNA (HOTAIR). The expression of HOTAIR was significantly increased in glioma cells compared with normal cells, and it exerted its function in a polycomb repressive complex 2-dependent manner. These results may provide novel approaches to therapeutically target PDCD4 and HOTAIR in patients with gliomas. IntroductionHuman gliomas are the most prevalent malignant neoplasms of the central nervous system, with an annual incidence of ~5/100,000 worldwide (1). Despite the use of aggressive surgery in combination with chemotherapy, biological therapy and radiotherapy, gliomas continue to be therapeutically challenging (2). For patients with glioblastoma, the relative 5-year survival rate is <5% (3). Novel therapies for the treatment of glioma are warranted; recent advances in the understanding of the molecular and biological nature of this disease may facilitate the development of successful therapeutics (4).PDCD4 protein was initially determined to be overexpressed during apoptosis, which subsequently suppresses tumorigenesis (5,6). Loss of PDCD4 expression is closely associated with the progression of a number of tumors, including glioblastomas (7), and kidney, ovarian and lung cancer (8-10). Low PDCD4 expression levels correlate with poor outcomes in patients with glioblastoma multiforme (11). The frequent loss of PDCD4 in glioblastoma multiforme is partly due to epigenetic silencing secondary to 5' cytosine-phosphate-guanine island methylation (12), in addition to overexpression of microRNA (miRNA)-21, which targets PDCD4 mRNA for degradation (13). Although several studies have examined PDCD4 in glioma, the detailed molecular mechanisms underlying the role of PDCD4 in glioma remain poorly understood.Long non-coding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides, which are involved in various important events, including transcriptional, epigenetic and post-transcriptional regulation (14,15). A previous study profiled the lncRNA homeobox transcript antisense RNA (HOTAIR), and the results demonstrated that HOTAIR was closely correlated with poor prognosis, molecular ...

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“…Temozolomide induces apoptosis by disrupting DNA transcription and inducing DNA damage (15). Despite aggressive treatment, glioblastoma patients commonly exhibit resistance to temozolomide treatment and generally survive no more than two years following diagnosis (3)(4)(5)(16)(17)(18). The migration and invasion of glioblastoma cells is a possible explanation for this resistance.…”

Section: Discussionmentioning

confidence: 99%

“…Despite advances in the treatment of glioblastoma, the prognosis for patients with newly diagnosed glioblastoma remains poor. The median survival of these patients was 14.6 months when treated with chemoradiotherapy with temozolomide, due to the high invasiveness and heterogeneity of glioblastoma (3,4). Currently, there are no effective therapeutic options to prevent temozolomide resistance.…”

Section: Introductionmentioning

confidence: 99%

Antitumor activity of 7-O-succinyl macrolactin A tromethamine salt in the mouse glioma model

Choi¹,

Lee²,

Joo³

et al. 2017

Oncology Letters

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Abstract. Chemoradiotherapy with temozolomide is the current standard treatment option for patients with glioblastoma. However, the majority of patients with glioblastoma survive for <2 years. Therefore, it is necessary to develop more effective therapeutic strategies for the treatment of glioblastoma. 7-O-succinyl macrolactin A tromethamine salt (SMA salt), a macrolactin compound, is known to possess an antiangiogenic activity. The present study investigated the antitumor effects of SMA salt in the treatment of glioblastoma by evaluating in vitro and in vivo antitumor effects of SMA salt in an experimental glioblastoma model. The antitumor effects of the drug on human glioblastoma U87MG, U251MG and LN229 cell lines were assessed using in vitro cell viability, migration and invasion assays. Nude mice with established U87MG glioblastoma were assigned to either the control or SMA salt treatment group. The volume of tumors and the duration of survival were also measured. SMA salt affected cell viability and caused a concentration-dependent inhibition effect on the migration and invasion of glioblastoma cell lines. Animals in the SMA salt treatment group demonstrated a significant reduction in tumor volume and an increase in survival (P<0.05). Treatment with SMA salt presented more cytotoxic effects as well as anti-migration and anti-invasion activity compared with the control group in vitro and in vivo. These results suggest that SMA salt has significant antitumor effects on glioblastoma.

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Immunotherapy of Diffuse Gliomas: Biological Background, Current Status and Future Developments

Cited by 2,988 publications

References 287 publications

Effector T-Cell Infiltration Positively Impacts Survival of Glioblastoma Patients and Is Impaired by Tumor-Derived TGF-β

Effector T-Cell Infiltration Positively Impacts Survival of Glioblastoma Patients and Is Impaired by Tumor-Derived TGF-β

Suppression of PDCD4 mediated by the long non-coding RNA HOTAIR inhibits the proliferation and invasion of glioma cells

Antitumor activity of 7-O-succinyl macrolactin A tromethamine salt in the mouse glioma model

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