Glioblastoma immune landscape remodeling following treatment with CD70-targeted CAR-T cells.
6 affiliations
- 1Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
- 2Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
- 3Department of Neurology, Medical Faculty Mannheim, Mannheim Center for Translation Neuroscience (MCTN), Heidelberg University, Mannheim, Germany.
- 4Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.
- 5Medicine, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany.
- 6Department of Neurology and Neurooncology Program, Heidelberg University Hospital, Heidelberg, Germany.
Abstract
Chimeric antigen receptor (CAR)-T cell therapy has shown limited efficacy in glioblastoma (GB), largely because of the immunosuppressive tumor microenvironment (TME). We have previously demonstrated that the ligand-based mCD70-directed construct mCAR27 specifically eliminates CD70⁺ GB cells in vitro, and induces durable tumor remission with prolonged survival in a syngeneic model of orthotopic GB. Despite the therapeutic promise of CD70 as a GB CAR-T cell target, the impact of CD70-directed CAR-T cells on the brain tumor immune landscape after target interception remains unexplored. Here, we independently confirmed a tumorigenic role for CD70 in murine GB by performing bulk RNA sequencing and in vivo experiments. Next, we applied single-cell RNA sequencing (scRNAseq) to decipher the transcriptome of GB-infiltrating immune cells in immunocompetent mice bearing CD70⁺ GB after intratumoral mCAR27 therapy. CAR-T cell treatment expanded adoptively transferred cells and was associated with increased endogenous Cd8⁺ T-cell infiltration, alongside a reduction in immunosuppressive populations, including Tregs and anti-inflammatory M2-like macrophages, but also subsets of dendritic and natural-killer cells. CD70 expression was detected on multiple GB-infiltrating immune subsets, notably Tregs and M2-like macrophages. Transcriptionally, mCAR27-mediated GB remission led to a coordinated downregulation of type-I interferon-stimulated genes and immunosuppressive mediators such as Arg1, Tgfbi, Cd274, Pdcd1lg2 and Lag3, coupled with upregulation of genes involved in inflammatory resolution, findings consistent with attenuation of GB-derived inflammatory stress and immunosuppression. Collectively, we showcase that CD70-directed CAR-T cell therapy remodels the post-treatment immune landscape towards resolution of inflammation and reduced immunosuppression, supporting sustained immune surveillance.
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BibTeX
@article{kourtesakis2026glioblastoma,
title = {{Glioblastoma immune landscape remodeling following treatment with CD70-targeted CAR-T cells.}},
author = {Alexandros Kourtesakis and Dennis Alexander Agardy and Clara Tejido Dierssen and Ling Hai and Dirk Carsten Frieder Hoffmann and Normann Mussnig and Ralph Sinn and Manuel Fischer and Andy Schacht and Michael Breckwoldt and Lukas Bunse and Tim Sauer and Michael Platten and Wolfgang Wick and Tobias Kessler},
journal = {Oncoimmunology},
year = {2026},
month = oct,
doi = {10.1080/2162402x.2026.2745295},
url = {https://europepmc.org/article/MED/42894313},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Glioblastoma immune landscape remodeling following treatment with CD70-targeted CAR-T cells.
AU - Alexandros Kourtesakis
AU - Dennis Alexander Agardy
AU - Clara Tejido Dierssen
AU - Ling Hai
AU - Dirk Carsten Frieder Hoffmann
AU - Normann Mussnig
AU - Ralph Sinn
AU - Manuel Fischer
AU - Andy Schacht
AU - Michael Breckwoldt
AU - Lukas Bunse
AU - Tim Sauer
AU - Michael Platten
AU - Wolfgang Wick
AU - Tobias Kessler
PY - 2026
DA - 2026/10/18
JO - Oncoimmunology
DO - 10.1080/2162402x.2026.2745295
UR - https://europepmc.org/article/MED/42894313
AB - Chimeric antigen receptor (CAR)-T cell therapy has shown limited efficacy in glioblastoma (GB), largely because of the immunosuppressive tumor microenvironment (TME). We have previously demonstrated that the ligand-based mCD70-directed construct mCAR27 specifically eliminates CD70⁺ GB cells in vitro, and induces durable tumor remission with prolonged survival in a syngeneic model of orthotopic GB. Despite the therapeutic promise of CD70 as a GB CAR-T cell target, the impact of CD70-directed CAR-T cells on the brain tumor immune landscape after target interception remains unexplored. Here, we independently confirmed a tumorigenic role for CD70 in murine GB by performing bulk RNA sequencing and in vivo experiments. Next, we applied single-cell RNA sequencing (scRNAseq) to decipher the transcriptome of GB-infiltrating immune cells in immunocompetent mice bearing CD70⁺ GB after intratumoral mCAR27 therapy. CAR-T cell treatment expanded adoptively transferred cells and was associated with increased endogenous Cd8⁺ T-cell infiltration, alongside a reduction in immunosuppressive populations, including Tregs and anti-inflammatory M2-like macrophages, but also subsets of dendritic and natural-killer cells. CD70 expression was detected on multiple GB-infiltrating immune subsets, notably Tregs and M2-like macrophages. Transcriptionally, mCAR27-mediated GB remission led to a coordinated downregulation of type-I interferon-stimulated genes and immunosuppressive mediators such as Arg1, Tgfbi, Cd274, Pdcd1lg2 and Lag3, coupled with upregulation of genes involved in inflammatory resolution, findings consistent with attenuation of GB-derived inflammatory stress and immunosuppression. Collectively, we showcase that CD70-directed CAR-T cell therapy remodels the post-treatment immune landscape towards resolution of inflammation and reduced immunosuppression, supporting sustained immune surveillance.
SN - 2162-4011
SN - 2162-402X
ER -