A Human Tumor-Immune Organoid Model of Glioblastoma

Baisiwala, S.; Fazzari, E.; Li, M. X.; Martija, A.; Azizad, D. J.; Sun, L.; Herrera, G.; Phan, T.; Monteleone, A.; Nathanson, D. A.; Wang, A. C.; Kim, W.; Everson, R. G.; Patel, K. S.; Liau, L. M.; Prins, R. M.; Bhaduri, A.

doi:10.1101/2025.06.16.660009

bioRxiv · 10.1101/2025.06.16.660009

A Human Tumor-Immune Organoid Model of Glioblastoma

Baisiwala, S.·Fazzari, E.·Li, M. X.·Martija, A.·Azizad, D. J.·Sun, L.·Herrera, G.·Phan, T.·Monteleone, A.·Nathanson, D. A.·Wang, A. C.·Kim, W.·Everson, R. G.·Patel, K. S.·Liau, L. M.·Prins, R. M.·Bhaduri, A.

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Abstract

A major obstacle to identifying effective therapies for the aggressive brain tumor glioblastoma is the lack of human-specific, immunocompetent models that reflect the human tumor microenvironment. To address this, we developed the immune-Human Organoid Tumor Transplantation (iHOTT) model. This is an autologous co-culture platform that integrates patient-derived tumor cells and matched peripheral blood mononuclear cells (PBMCs) within human cortical organoids, enabling the study of the patient-specific immune response to the tumor and tumor-immune interactions. This platform preserves tumor and immune populations, immune signaling, and cell-cell interactions observed in patient tumors. Treatment of iHOTT with pembrolizumab, a checkpoint inhibitor, mirrored cell type shifts and cell interactions observed in patients. TCR sequencing further revealed pembrolizumab-driven expansion of stem-like CD4-T-cell clonotypes exhibiting patient-specific repertoires. These findings establish iHOTT as a physiologically relevant platform for exploring autologous tumor-immune interactions and underscore the critical need for antigen-targeted strategies to enhance immunotherapy in glioblastoma.

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Baisiwala, S., Fazzari, E., Li, M. X., Martija, A., Azizad, D. J., Sun, L., Herrera, G., Phan, T., Monteleone, A., Nathanson, D. A., Wang, A. C., Kim, W., Everson, R. G., Patel, K. S., Liau, L. M., Prins, R. M., Bhaduri, A.. 2025-06-20. A Human Tumor-Immune Organoid Model of Glioblastoma. https://doi.org/10.1101/2025.06.16.660009

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