Mitoxantrone alters CD24/Siglec-10 expression in malignant brain tumor models.

Abstract

Medulloblastoma and glioblastoma are the most common malignant primary brain tumors in children and adults, respectively. Tumor-associated macrophages and microglia are key non-cancerous cell types in these tumors. These cells interact with CD24, a so called "don't eat me signal" expressed on tumor cells, through Siglec-10, a receptor that contributes to immune evasion by promoting an immunosuppressive environment. The CD24/Siglec-10 interaction in context of malignant brain tumors has been scarcely studied.In silico analyses reveal that CD24 gene expression correlates with specific gene signatures associated with prognosis in both medulloblastoma and glioblastoma. In both human- and mouse brain tumors, Siglec-10cells co-express the microglia-associated molecule TREM2. Treatment with mitoxantrone as an immunogenic cell-death-inducing cytostatic agent led to a dose-dependent reduction in cell viability and cell surface CD24 levels in both murine and human brain tumor cell cultures. Intratumoral mitoxantrone administration in a murine CD24-high glioma model extended survival, decreased tumor size, reduced Siglec-10/TREM2cell populations, and increased anti-tumor CD8cells. These findings suggest that targeting the CD24/Siglec-10 axis with mitoxantrone may modulate the tumor microenvironment and enhance anti-tumor immunity. Keywords: CD24, Siglec-10, Mitoxantrone, Malignant brain tumor, Immunotherapy.