Abstract
Glioblastoma, the most aggressive form of glioma, has a 5-year survival rate of <5%. While radiation and immunotherapies are routinely studied in the murine Gl261 glioma model, little is known about its inherent immune response. This study quantifies the temporal and spatial localization of immune cell populations and mediators during glioma development. Eight-week old male C57Bl/6 mice were orthotopically inoculated with 1x106 Gl261 cells and tumor morphology, local and systemic immune cell populations, and plasma cytokines/chemokines assessed at day 0, 1, 3, 7, 14, and 21 post-inoculation by magnetic resonance imaging, chromogenic immunohistochemistry, multiplex immunofluorescent immunohistochemistry, flow cytometry and multiplex immunoassay respectively. From day 3 tumors were distinguishable with >30% Ki67 and increased tissue vascularization (p<0.05). Increasing tumor proliferation/malignancy and vascularization were associated with significant temporal changes in immune cell populations within the tumor (p<0.05) and systemic compartments (p = 0.02 to p<0.0001). Of note, at day 14 16/24 plasma cytokine/chemokines levels decreased coinciding with an increase in tumor cytotoxic T cells, natural killer and natural killer/T cells. Data derived provide baseline characterization of the local and systemic immune response during glioma development. They reveal that type II macrophages and myeloid-derived suppressor cells are more prevalent in tumors than regulatory T cells, highlighting these cell types for further therapeutic exploration.
Highlights
High grade gliomas (HGG) remain a debilitating and early fatal disease
In this study we provide a comprehensive characterization of the immune response in the murine syngeneic Gl261 glioma model both temporally and spatially
The current study shows that there are dynamic immunomodulatory effects in the local and systemic compartments during glioma development and warrants comprehensive tracking during the preclinical assessment of novel therapeutics
Summary
High grade gliomas (HGG) remain a debilitating and early fatal disease. Almost 60% of gliomas are glioblastomas (GBM) which develop de novo (primary GBM), though secondary GBM. Purchase of the VECTRA3 microscope was supported by The James N Kirby Foundation The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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