Abstract
Glioblastoma induces immunosuppressive effects by several, redundant mechanisms, TGF-β/VEGF signalling pathway, IL-2Rα/CD25-mediated, CTLA-4/PD-1/PD-L1 immune checkpoint interaction and STAT3 activation. All of these mechanisms have been investigated as potential therapeutic targets for glioblastoma treatment in various clinical and preclinical trials. Tregs are a subset of CD4+ T cells that infiltrate tumours. They suppress proliferation and activity of effector T cells. Treg frequency increases with increasing WHO grade. Tregs and effector T cells express co-inhibitory PD-1 receptor and in melanoma can be divided into 3 compartments by expression levels of FoxP CD45RA and CD25;1. FoxP3(lo)CD45RA+CD25(lo) – naïve Treg cells,2. FoxP3 (hi)CD45RA-CD25(hi) – highly suppressive,3. FoxP3 (lo)CD45RA-CD25(lo) – non-suppressive. Serum from 34 high grade and 34 low grade glioma patients, were analysed for the concentration of TGF-β, PD1 and its ligand PD-L1 along with 33 control sera from non-cancerous patients using an ELISA technique. Tissue samples embedded in paraffin wax from the same patients were also examined for the presence of IL-2Rα using immuno-histochemistry. Treg cells from these patients were isolated from buffy coat preparations and were examined using a flow cytometric technique. There were significant differences in the measured analytes between sera of glioma patients of low and high grade and non-cancerous control patients. Tumour tissue also revealed increased expression of the IL-2 receptor. Treg cells displayed compartmentalisation into several subtypes. These results suggest that specific protein levels can be used to detect and confirm a glioma diagnosis as well as to distinguish between low and high grade gliomas. These results may also be used to predict tumour recurrence and transformation between low and high grade gliomas. There was an interesting up-regulation of the IL-2 receptor on tumour cells which indicates that these cells may have a role in immunosuppression and immunosurveillance.
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