Immunotherapy against the radial glia marker GLAST effectively triggers specific antitumor effectors without autoimmunity

Abstract

The glutamate-aspartate transporter GLAST is a radial glia marker that is highly expressed in GL261 stem-like cells (GSCs). To target GLAST, we treated glioma-bearing mice with three subcutaneous injections of four GLAST peptides emulsified with Montanide ISA-51 in association with granulocyte macrophage colony-stimulating factor (GM-CSF) injections. Vaccination with GLAST peptides significantly prolonged survival, effectively enhanced systemic T-cell and NK-cell responses and promoted robust antitumor cytotoxicity. GLAST expression significantly decreased in gliomas from immunized mice, as evaluated by histological analysis and real-time PC R (RT-PC R). Moreover, the immunization protocol led to the upregulation of interferonγ (INFγ) and tumor necrosis factora (TNFa) as well as to the downregulation of transforming growth factor (TGF) β1 and β2 in the tumor. Beyond these changes, gliomas from immunized mice exhibited an increased recruitment of NK cells and antigen-specific CD8+ T cells expressing the tumor homing molecule VLA-4, as well as a local chemotactic gradient featuring expression of CXCL10 (which may be responsible for the recruitment of CTLs), CC L3, CC L4 and CC L5 (which are involved in NK-cell migration), and NKG2D ligand on glioma cells. Importantly, although GLAST is expressed in the central nervous system, autoimmune reactions were not observed in immunized mice. Altogether, these results support the contention that GLAST may constitute a glioma antigen against which immune responses can be efficiently induced without major safety concerns. © 2012 Landes Bioscience.