Developing a Novel Organoid Model to Investigate Tumor-immune Interactions in Glioblastoma

Introduction: Glioblastoma is an aggressive brain cancer with poor prognosis, primarily due to its therapeutic resistance and ability to evade immune detection through an immunosuppressive microenvironment. Despite promising immunotherapies, this tumor continues to evade all current therapeutic strategies, highlighting the need for better models to study tumor-immune interactions. Our goal was to create a model to study these interactions and evaluate immunotherapy effectiveness.

Methods: We developed a co-culture organoid model combining patient-derived glioblastoma (IDH-WT) cells and immune cells, both obtained during tumor resection surgery. These co-cultures were subsequently analyzed with single-cell sequencing, chemokine and cytokine profiling, and flow cytometry to capture complex cellular and molecular interactions.

Results: Our model successfully maintained tumor heterogeneity and immune cell subtypes, with T-cell enrichment when co-cultured with tumor cells. We observed that naive immune cells responded to tumor presence by releasing chemokines and cytokines similar to the profiles observed in glioblastoma patient samples. Notably, tumor cells demonstrated a shift toward neuronal identity in the presence of immune cells, suggesting that the co-culture model allows for observation of microenvironmental effects on cell fate specification.

Conclusion : This organoid-based co-culture system supports the growth of tumor and immune cell populations, providing a high-fidelity platform by which to examine mechanisms of treatment resistance and immunotherapeutic responses. This model fills a critical gap in glioblastoma research by enabling nuanced study of tumor-immune interactions and potential mechanisms of immunotherapy resistance.