Article
T-cell infiltration impact on GBM patient survival and its impairment by TGF-β1 and -β2
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Authors
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Jennifer Lohr
- Universität Heidelberg, Neurochirurgische Klinik, Heidelberg, Deutschland
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Rezvan Ahmadi
- Universität Heidelberg, Neurochirurgische Klinik, Heidelberg, Deutschland
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Andrea Huppertz
- Universität Heidelberg, Neurochirurgische Klinik, Heidelberg, Deutschland
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Stefan Grau
- Universität München, Klinikum Großhadern, Neurochirurgische Klinik, München, Deutschland
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Christel Herold-Mende
- Universität Heidelberg, Neurochirurgische Klinik, Heidelberg, Deutschland
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Andreas Unterberg
- Universität Heidelberg, Neurochirurgische Klinik, Heidelberg, Deutschland
| Published: | September 16, 2010 |
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Outline
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Objective: In the last decades, immunotherapeutical approaches have been successfully designed with the aim of inducing anti-glioma T-cell responses. As a prerequisite for a therapeutical effect, T-cells need to overcome the endothelial barrier. The purpose of this study was to investigate whether pre-existing infiltration of effective- and immunosuppressive T-cell subsets have an impact on overall survival of GBM patients. Moreover, we attempted to identify mechanisms by which gliomas disturb transmigration of T-cells.
Methods: To asses T-cell infiltration, cryostate sections of glioma patients (n=123) were costained for T-cell markers CD3, CD8 and Foxp3. Tissue lysates were quantified by ELISA for amounts of different cytokines proven to be involved into glioma angiogenesis. Furthermore, the influence of the most highly expressed cytokines was studied in a functional in vitro coculture model consisting of GBM-derived endothelial cells and T-cells from the same donor.
Results: Evaluation of glioma tissues was performed with a newly developed method, achieving a data set similar to flow cytometry. Comparison with clinical data revealed that GBM patients, who live longer than the average survival time of 15 months, show higher intratumoral levels of effector-T-cells (p=0,01). It was remarkable that the presence of regulatory T-cells and T-suppressor cells, which impair T-effector tasks, did not influence patients' survival. To investigate whether tumor-secreted factors regulate T-cell transmigration, we analyzed VEGF, HGF, bFGF, TGF-β1 and TGF-β2 in a functional assay. Interestingly, only TGF-βs impaired T-cell transmigration (p<0,01). Moreover, a blockage of TGF-β receptor signaling reversed the inhibitory effect of TGF-β1 as well as TGF-β2.
Conclusions: Our results indicate a relationship between T-cell infiltration and survival in GBMs. In addition to the known immunosuppressive properties of TGF-β1 and -β2, we discovered a new mechanism by which gliomas may prevent tumor rejection. Studies on a mouse model are currently under way to confirm the in vitro findings.
