Intracranic injection of CIITA-driven MHC-II positive glioblastoma cells induces an effective anti-tumor immune response in vivo: implication for new therapeutic strategies against the glioblastoma

Background: Glioblastoma (GBM) is the most aggressive brain tumor with dismal prognosis despite standard of care including surgery, radiotherapy, and chemotherapy. The recent success of immunotherapy for other aggressive cancers has given new hope for extending it to GBM as well. However, the main challenges of immunotherapy for GBM are the blood brain barrier that strongly limits access to the intracranial location and relative immunosuppressive tumor microenvironment observed in brain tumor tissue. Our previous studies showed that CIITA-induced MHC class II expression in tumor cells of distinct histological origin renders these cells surrogate antigen presenting cells of their own tumor antigens, leads to a Th1 polarization of the tumor microenvironment, tumor rejection and acquisition of specific anti-tumor memory. Here we report the unprecedented positive results of our approach to GBM. Methods: Immunocompetent C57BL/6 mice were implanted intracranially (i.c.) in one hemisphere with the GL261 glioma parental tumor cells (GL261pc) or the same cells transfected with CIITA (GL261-CIITA). At 3, 7, 14 and 21 days post-injection (p.i.) mice were sacrified and the brains were analyzed for the presence of the tumor and the tumor infiltrating cells by immunohistochemistry. To assess acquisition of protective anti-tumor immunity GL261-CIITA injected mice at 21 days post injection were injected in the opposite hemisphere with GL261pc and sacrified 21 days after the last injection. The presence of both parental and CIITA tumor and the cellular infiltrate was assessed as specified above. Results: GL261-CIITA tumors are rejected or significantly reduced in their growth compared to GL261pc tumors. This correlates with a cellular infiltrate mostly represented in GL261-CIITA injected mice by both CD4 and CD8 T lymphocytes. Preimplantation of GL261-CIITA tumor cells results in complete rejection or strong growth retardation of GL261pc tumor cells in the opposite hemisphere. Conclusions: GL261-CIITA cells are potent stimulators of an adaptive immune response in vivo, able to protect the mouse from tumor take. GL261-CIITA tumors vaccination prevented or strongly reduced GL261pc tumor growth in the opposite hemisphere, suggesting that an effective intracranial anti-tumor immune response can be established as a consequence of Th cell restricted-recognition of GBM-specific antigens.