A human tumor-immune organoid model of glioblastoma
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.
Authors
- David A. Nathanson (ORCID: https://orcid.org/0000-0002-4919-9159)
- Richard G. Everson (ORCID: https://orcid.org/0000-0003-2809-3061)
- Gilbert Herrera
- Matthew Li (ORCID: https://orcid.org/0009-0009-0539-7389)
- Antoni Martija (ORCID: https://orcid.org/0000-0003-4293-6002)
- Ryan L. Kan (ORCID: https://orcid.org/0000-0003-1162-8365)
- Elisa Fazzari (ORCID: https://orcid.org/0000-0001-5651-8587)
- Aparna Bhaduri (ORCID: https://orcid.org/0000-0003-4625-6899)
- A. Hongjun Wang
- Linda M. Liau (ORCID: https://orcid.org/0000-0002-4053-0052)
- Daria Azizad (ORCID: https://orcid.org/0009-0006-7015-9027)
- Amber Monteleone
- Kunal S. Patel
- Trinh Phan
- Robert M. Prins
- Lu Sun
- Shivani Baisiwala
- Won Kim
Institutions
- University of California, Los Angeles (US)
- UCLA Health (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2026-01-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.116790
- Citations
- 2
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 73.86
Funders
- Alexander and Margaret Stewart Trust
- McKnight Foundation
- Sontag Foundation
- California Institute of Technology
- Rose Hills Foundation
- Swim Across America
- National Institutes of Health
- National Cancer Institute
- Jonsson Comprehensive Cancer Center
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles