Evaluating the NFPp10a/NF5310 glioblastoma model as a faithful avatar for screening tumour microenvironment–targeted therapies

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Despite positive outcomes for novel targeted therapy screens in preclinical studies, the majority of follow on GBM clinical trials fail to meet their primary endpoints. This translational gap is partly due to models that do not accurately recapitulate the human GBM-TME and therefore fail to accurately predict patient treatment response. Here, we investigated the NFPp10a/NF5310 syngeneic mouse model of mesenchymal GBM, to assess its translational relevance for evaluating TME-targeting agents. Young and aging C57BL/6 mice bearing orthotopic NFPp10a/NF5310-Luc2 tumours underwent treatment with temozolomide (TMZ), tumour resection, anti-PD1 checkpoint blockade, and/or regorafenib (REGO). TME composition was evaluated using the murine microenvironment cell population (mMCP) counter method and multiplexed immunohistochemistry (multiple iterative labelling by antibody neodeposition). To assess translational relevance and conserved human response patterns, immune cell composition and gene expression changes were directly compared to primary human mesenchymal GBM tumours via further hypothesis generating MILAN analysis and by studying publically available ICI clinical trial data. NFPp10a/NF5310-Luc2 tumour-bearing mice showed resistance to monotherapy and neoadjuvant anti-PD1, with limited response also observed to REGO treatment. mMCP analysis revealed modest increases in CD8+ T-cells, B cells, and monocytes following anti-PD1 and REGO treatment. MILAN analysis further indicated increased cytotoxic T-cells following anti-PD1 therapy. Comparison to untreated-primary GBM and ICI-treated human GBM suggested similar exhausted CD8+ T-cell phenotypes, suggesting the NFPp10a/NF5310 TME reflects the mesenchymal GBM T-cell compartment. Overall, the NFPp10a/NF5310 model recapitulates the GBM-TME architecture and therapeutic resistance patterns observed in human GBM, supporting its use in evaluating select TME-targeting therapies. The NFPp10a/NF5310 glioblastoma model demonstrates clinically relevant response patterns and key tumour microenvironment features of mesenchymal glioblastoma, supporting its utility as a translational platform for therapeutic development.

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