Transcranial Agonism of CD40 and ICOS Promotes Meningeal Immunity and Control of Glioblastoma

Abstract

INTRODUCTION: Glioblastomas generate an immunosuppressive microenvironment that limits antitumor immune responses. METHODS: We used the SB28 model of glioblastoma in C57BL/6J (B6) mice, which is a poorly immunogenic tumor with a lower mutational load than other many glioblastoma cell lines used in rodents. We stereotactically injected 7,000 SB28 cells at a depth of 1 mm into the neocortex of 8- to 10-week-old mice. At day 7, a carboxymethylcellulose gel containing 100 µg of agonistic anti-ICOS and 200 µg anti-CD40 were injected transcranially (i.e., under the scalp) of mice. Control mice received corresponding isotype control antibodies. Meningeal whole mounts were then stained using immunohistochemistry and imaged by confocal microscopy. RESULTS: Transcranial agonism of CD40 and ICOS generated a markedly enhanced and more localized meningeal immune response against SB28 tumors than intravenous agonism. Specifically, transcranial treatment promoted formation of CD4 T cell and B cell clusters in the meninges as well as increased production of class-switched immunoglobulins. These clusters were also associated with reduced tumor size at day 14. CONCLUSIONS: Our results demonstrate that transcranial delivery of antibodies against CD40 and ICOS can drive a local humoral immune response against an immunologically silent SB28 glioblastoma. We postulate that application of these agonistic antibodies in combination with a tumor neoantigen will further enhance tumor control and may offer a possible treatment modality in human glioblastoma patients.