Myeloid-derived immunosuppression of chimeric antigen receptor T cells in the neuronal microenvironment of glioblastoma.
Overview
- Department of Neurosurgery, Medical Center - University of Freiburg, Breisacher Straße 64, 79106, Freiburg, Germany
- Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany
- Department of Neurology, Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland
- Department of Neurosurgery, University of Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schwabachanlage 6, 91054, Erlangen, Germany
- Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany
- Center for NeuroModulation (NeuroModul), University of Freiburg, Freiburg, Germany
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, USA
- German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany
Abstract
Background: Chimeric antigen receptor (CAR)-T cell therapy remains largely ineffective in glioblastoma (GB), where a highly immunosuppressive microenvironment and tumor heterogeneity impair therapeutic durability.
Methods: Using a human neocortical brain slice model that preserves the complex GB microenvironment, we profiled interactions between natural killer group 2D (NKG2D) CAR-T cells and tumor ecosystems via PIC-seq, spatial transcriptomics, and gene regulatory network reconstruction.
Results: CAR-T cells showed an early but unsustained tumor-suppressive effect in the slice model. Single-cell profiling revealed that CAR CD8 T cells adopt an effector-skewed activation state accompanied by coordinated upregulation of checkpoint receptors and an exhaustion-associated transcription factor program. These transcriptional changes were linked to ligand-receptor signaling interactions between CAR-T cells and myeloid populations. Tumor-associated macrophages displayed enhanced phagocytic programs and spatially co-localized with mesenchymal-like GB cells within hypoxic regions. Gene regulatory network analysis identified MAF and BACH2 as candidate regulators of CD8 T cell state, with MAF enriched in CAR CD8 T cells exhibiting exhaustion-like features, and BACH2 enriched in Mock CD8 T cells consistent with less differentiated programs. In silico perturbation analyses further suggested a reciprocal effect of MAF and BACH2 on CD8 T cell transcriptional trajectories.
Conclusions: These data map the microenvironmental and transcriptional changes associated with rapid CAR-T cell dysfunction in GB and identify candidate pathways and regulators that may be leveraged to engineer more durable cellular therapies.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- figshare:31976522, at figshare; found in DataCite
- figshare:31976525, at figshare; found in DataCite
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Version 1, 30 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 9 authors, 6 keywords, 11 MeSH terms, 1 funder, 0 references.
Cite
This paper
Zhang, J., von Ehr, J., Look, T., Benotmane, J. K., Neidert, N., Kueckelhaus, J., Weiss, T., Heiland, D. H., & Yabo, Y. A. (2026). Myeloid-derived immunosuppression of chimeric antigen receptor T cells in the neuronal microenvironment of glioblastoma. BMC medicine, 24(1), 212. https://
BibTeX
@article{zhang2026myeloi
author = {Zhang, Junyi and von Ehr, Jasmin and Look, Thomas and Benotmane, Jasim Kada and Neidert, Nicolas and Kueckelhaus, Jan and Weiss, Tobias and Heiland, Dieter Henrik and Yabo, Yahaya A},
title = {{Myeloid-derived immunosuppression of chimeric antigen receptor T cells in the neuronal microenvironment of glioblastoma}},
journal = {BMC medicine},
year = {2026},
month = mar,
volume = {24},
number = {1},
pages = {212},
publisher = {BioMed Central},
issn = {1741-7015},
doi = {10.1186/
url = {https://
pmid = {41827001},
pmcid = {PMC13063468}
}
RIS
TY - JOUR
AU - Zhang, Junyi
AU - von Ehr, Jasmin
AU - Look, Thomas
AU - Benotmane, Jasim Kada
AU - Neidert, Nicolas
AU - Kueckelhaus, Jan
AU - Weiss, Tobias
AU - Heiland, Dieter Henrik
AU - Yabo, Yahaya A
TI - Myeloid-derived immunosuppression of chimeric antigen receptor T cells in the neuronal microenvironment of glioblastoma
T2 - BMC medicine
J2 - BMC Med
PY - 2026
DA - 2026/
VL - 24
IS - 1
SP - 212
SN - 1741-7015
PB - BioMed Central
DO - 10.1186/
UR - https://
LA - en
ER -
CSL-JSON
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