Glioma Stem Cells Upregulate CD39 Expression to Escape Immune Response through SOX2 Modulation

SIMPLE SUMMARY: Glioblastoma is the most malignant tumor of the central nervous system. Glioma stem cells are the cause of adverse outcomes such as early recurrence and low overall survival in glioma patients. Targeting glioma stem cells is considered a promising anti-glioma strategy, Although CD39 plays a key role in the initiation and regulation of DC-mediated antigen-specific immune responses, its impact on GSCs is unclear. Therefore, we systematically investigated the effect of CD39 on extracellular ATP levels, dendritic cell recruitment and T cell killing in glioma stem cells. The molecular mechanism by which SOX2 binds to the CD39 promoter to regulate extracellular ATP levels, and evaluated the immune response enhanced by inhibition of CD39 after ADM treatment in a mouse glioma model. We suggest that CD39 is an effective target for glioma immunotherapy. ABSTRACT: Ectonucleotidase CD39 hydrolyzing extracellular ATP (eATP) functions as a key modulator of immune response in the tumor microenvironment, yet the role of CD39 in contributing tumor stem cells in a more immunosuppressive microenvironment remains elusive. Here we report that the upregulation of CD39 is crucial for the decrease of extracellular ATP concentration around glioma stem cells (GSCs) to maintain an immunosuppressive microenvironment. Adriamycin (ADM) is able to promote the release of ATP, which recruits dendritic cells (DCs) to phagocytose GSCs. CD39 inhibition further increased extracellular ATP concentrations following ADM treatment and DCs phagocytosis. In addition, GSCs upregulated CD39 expression by SOX2-binding CD39 promotor. In mouse tumor models, the combination of ADM and CD39 blockade increased immune cell infiltration and reduced tumor size. These findings suggest that GSCs upregulate CD39 expression by their biological characteristics to maintain an immunosuppressive microenvironment, and CD39 inhibition supplies a favorable tumor microenvironment (TME) for immunotherapeutic intervention and enhances the immune response induced by chemotherapy.