Introduction: Glioblastoma (GBM) and other intracranial neoplasms are restricted to the periphery by the blood brain barrier (BBB). There are other neuroanatomical barriers, such as the meningeal barrier, which engender fenestrated vessels and may be a location to bypass the BBB. Here, we study the potential role of meningeal immune cells in eradicating GBM.
Methods: C57BL/6J mice were stereotactically injected with syngeneic SB28 (glioblastoma) cell lines. Mice were treated with either isotype control or a CD40 agonist to stimulate CD4+ T-cells and B-cells. Meningeal whole mounts, brains and spleens were also collected and analyzed by confocal microscopy and high parameter flow cytometry. Survival studies were carried out in syngeneic and non-syngeneic models in order to quantify survival and humoral response.
Results: CD40-agonism promoted the development of tertiary-lymphoid structures in the meningeal space. This robust expansion of meningeal B-cells and CD4+ T-cells led to decreased overall tumor size and increased IgG staining in the peritumoral space. There was also a robust meningeal plasma cell response in the meningeal space. Treating mice with a CD40 agonist led to an increased overall survival in the syngeneic model and complete tumor rejection in the non-syngeneic model
Conclusion : Other neuroanatomical barriers are potential locations to bypass the blood brain barrier. By giving a CD40 agonist and boosting humoral immunity, we were able to induce the creation of tertiary lymphoid structures in the dura mater and ultimately promote a Th2 response against GBM. We were also able to prolong survival and lead to tumor rejection in non-syngeneic model Our data highlights the benefit of tumors abutting the meningeal space and the utility of promoting humoral immunity for immunotherapy
