Artikel
Comprehensive analysis of immunology in recurrent glioblastoma multiforme
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Veröffentlicht: | 9. Juni 2017 |
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Gliederung
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Objective: The biology of recurrent glioblastoma is a dynamic process influenced by selection pressure induced by different antitumoral therapies. The characteristics of these biological processes have been rarely explored, which complicates treatment. Checkpoint-inhibition (PD1/PD-L1 Inhibition) is a hallmark of immunotherapy, which is being investigated for recurrent GBM in ongoing clinical trials. The purpose of this study was to analyse the PD-L1 expression in de-novo/recurrent glioblastoma multiforme and to explore associated genetic alterations.
Methods: 105 tissue samples of 56 glioblastoma patients were acquired by neuronavigation-guided resection between 2011 and 2014 in the Department of Neurosurgery, Medical Center University of Freiburg. Comprehensive transcriptional network analysis was performed by expression array data of 49 patients and validated by available data sets (TCGA and Bai et al.). Quantification of the PD-L1 level was performed by immunohistochemistry, immunofluorescence, western blot and qRT-PCR.
Results: Comprehensive transcriptional network analysis showed a strong connection between MAPK pathway activation and increased level of PD-L1. Additionally, PD-L1 expression was found to be associated with mesenchymal gene expression and immune response pathway up-regulation. However, the immune related pathways were down-regulated in recurrent glioblastoma. Recurrent GBM showed decreased mRNA expression-levels of PD-L1 in comparison to de-novo tumors. These findings were validated by additional immunostainings and western blot analysis. A multivariate regression model showed a significantly lower PD-L1-expression in recurrent glioblastoma associated with an extended temozolomide treatment.
Conclusion: We showed that PD-L1 expression and immune related pathway activation are reduced in recurrent GBM in comparison to de-novo GBM. Additionally, patients who received an extended dose of temozolomide chemotherapy showed a significantly lower level of PD-L1 expression in the recurred tumour stage. Our findings may therefore provide an explanation for reduced effectiveness of immunotherapy in recurrent GBM.