Abstract
Simple SummaryGlioblastoma (GB) is an aggressive brain tumour with poor survival. Tumour microenvironment is a key element in GB evolution and response to therapy. We assessed presence and phenotypes of microglia/macrophages in preclinical GL261-GB microenvironment under Temozolomide (TMZ) treatment to unveil its possible relationship with MRSI-detected metabolomics changes. Microglia/macrophage polarisation towards an anti-tumour phenotype prevailed in TMZ-treated tumours. Since microglia/macrophages can represent 30–40% of the GB tumour volume, they must contribute the metabolomic pattern change. PD-L1 expression also correlated with the anti-tumour microglia/macrophage phenotype. These results highlight the potential of MRSI-detected metabolomics as non-invasive biomarker for immune system action.Glioblastomas (GB) are brain tumours with poor prognosis even after aggressive therapy. Previous work suggests that magnetic resonance spectroscopic imaging (MRSI) could act as a biomarker of efficient immune system attack onto GB, presenting oscillatory changes. Glioma-associated microglia/macrophages (GAMs) constitute the most abundant non-tumour cell type within the GB and can be polarised into anti-tumour (M1) or pro-tumour (M2) phenotypes. One of the mechanisms to mediate immunosuppression in brain tumours is the interaction between programmed cell death-1 ligand 1 (PD-L1) and programmed cell death-1 receptor (PD-1). We evaluated the subpopulations of GAMs in responding and control GB tumours to correlate PD-L1 expression to GAM polarisation in order to explain/validate MRSI-detected findings. Mice were evaluated by MRI/MRSI to assess the extent of response to treatment and with qPCR for GAMs M1 and M2 polarisation analyses. M1/M2 ratios and PD-L1 expression were higher in treated compared to control tumours. Furthermore, PD-L1 expression was positively correlated with the M1/M2 ratio. The oscillatory change in the GAMs prevailing population could be one of the key causes for the differential MRSI-detected pattern, allowing this to act as immune system activity biomarker in future work.
Highlights
IntroductionGlioblastoma (GB) is the most frequent primary central nervous system malignancy in adults
Our results confirm that TMZ administered in an immune-enhancing metronomic schedule increases the GB-associated microglia/macrophage population infiltrating the tumour
The M2/Gliomaassociated microglia/macrophages (GAMs) ratio was shown to be remarkably lower in responding IMSTMZ-treated mice, while the M1/M2 ratio was significantly higher when compared to vehicle-treated mice
Summary
Glioblastoma (GB) is the most frequent primary central nervous system malignancy in adults These tumours have poor prognosis, which has not significantly improved creativecommons.org/licenses/by/ 4.0/). The implication of the immune system in cancer surveillance and therapy response is widely accepted [3] This is especially relevant in GB, since GB cells have the capacity for creating an immunosuppressive microenvironment and employ various methods to escape immune surveillance through several pathways [4]. Understanding these strategies and the biology of such tumour microenvironment will be helpful for developing novel therapeutic approaches and follow-up methods, which should lead to improved prognosis for GB patients
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