A human tumor-immune organoid model of glioblastoma
Shivani Baisiwala, Elisa Fazzari, Matthew Li, Antoni Martija, Daria Azizad, Lu Sun, Gilbert Herrera, Trinh Phan, Amber Monteleone, Ryan L. Kan, David A. Nathanson, A. Hongjun Wang, Won Kim, Richard G. Everson, Kunal S. Patel, Linda M. Liau, Robert M. Prins, Aparna Bhaduri
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, an autologous co-culture platform that integrates patient-derived tumor cells and matched peripheral blood mononuclear cells within human cortical organoids to enable the study of patient-specific immune responses 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, mirrors cell-type shifts and cell-cell interactions observed in patients. T cell receptor (TCR) sequencing further reveals 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 need for antigen-targeted strategies to enhance immunotherapy in glioblastoma.