CIITA-modified glioblastomas vaccinate and induce cross-protection against heterologous wild-type glioblastomas

Background: Glioblastoma (GBM) is a highly malignant brain tumor with poor outcome, despite current therapies. CIITA-modified tumor cells, capable of presenting antigens via MHC-II, show promise in eliciting effective antitumor immune responses. The efficacy of the CIITA-based vaccination strategy has been previously demonstrated using the GL261 murine GBM model. This study aimed at verifying whether a different GBM model, the CT-2A cells, more closely resembles human GBM, could follow the same rule and importantly share cross immunity with GL261. Methods: To assess tumor growth and immune response, immunocompetent mice were injected intracranially with either CT-2A or CIITA-modified CT-2A (CT-2A-CIITA) cells, and brain tissues were examined histologically. Additionally, mice vaccinated with GL261-CIITA cells were subsequently challenged with parental CT-2A cells in the opposite hemisphere, followed by immunohistochemical analysis of brain tissues. Results: Results indicated that CT-2A-CIITA cells were either rejected or exhibited delayed tumor growth in immunocompetent mice. Furthermore, mice previously vaccinated with GL261-CIITA cells demonstrated efficient rejection of CT-2A tumors, suggesting the induction of cross-protective immunity. This immune response was associated with a shift from an immunosuppressive to an immunogenic tumor microenvironment, implying the development of adaptive immunity against shared tumor antigens. Conclusions: In conclusion, these findings support the broader applicability of CIITA-based vaccination against GBM and provide the first evidence of shared immunogenic antigens between two distinct murine GBM models. This discovery opens avenues for identifying common tumor antigens through immunopeptidomics, which could inform future immunotherapeutic strategies for glioblastoma.