PD-1 Blockade-Induced DKK1 Expression by CD8+ T Cells Promotes Blood-Brain Barrier Permeabilization.
Overview
13 affiliations
- Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
- Rappaport Technion Integrated Cancer Center, Technion - Israel Institute of Technology, Haifa, Israel
- Department of Neurology, Rambam Healthcare Campus, Haifa, Israel
- Biomedical Core Facility, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
- Department of Neuroscience, Monash University, Melbourne, Australia
- Department of Psychiatry, Rambam Healthcare Campus, Haifa, Israel
- Department of Radiology Rambam Healthcare Campus, Haifa, Israel
- Oncohost LTD., Binyamina, Israel
- Department of Oncology, Rambam Healthcare Campus, Haifa, Israel
- Diagnostic and Interventional Radiology with Nuclear Medicine, Thoraxklinik, University of Heidelberg, Heidelberg, Germany
- Translational Lung Research Center (TLRC) at German Center for Lung Research (DZL), Heidelberg, Germany
- Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany
- Department of Medical Oncology, Thorax Clinic, Heidelberg, Germany
Abstract
Anti–PD-1 therapy benefits a subset of patients with brain metastasis (BrM); however, heterogeneous responses imply an incomplete understanding of the brain−immune ecosystem. To elucidate host-driven determinants of this variability, we performed single-cell RNA sequencing to characterize the brain microenvironment. Although anti–PD-1 induced robust antitumor immune activation, it uniquely, among all immune checkpoint inhibitors (ICI) tested, compromised blood–brain barrier (BBB) integrity. This permeabilization was mediated by DKK1-expressing activated CD8+ T cells through the induction of β-catenin/
Significance: Our study demonstrates that PD-1 blockade induces DKK1 expression in activated CD8+ T cells, leading to BBB permeabilization. This previously unrecognized host-driven mechanism may explain heterogeneous intracranial responses to immunotherapy and identifies BBB modulation as a therapeutic opportunity to enhance drug delivery and efficacy for BrM.
See related commentary by Karreman and Winkler, p. 831
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Version 2, 28 September 2026
- Publisher: n/a → American Association for Cancer Research
Version 1, 28 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 20 authors, 10 MeSH terms, 1 funder, 49 references, 6 RRIDs.
Cite
This paper
Deo, A., Levin, S., Buxbaum, C., Benguigui, M., Manobla, B., Saar, G., Bosak, N., Bergmann, E., Eran, A., Grinfeld, A., Harel, M., Lahav, C., Raviv, Z., Daher, S., Zer, A., Reuter, J. H., Heuβel, C. P., Christopoulos, P., Yizhak, K., & Shaked, Y. (2026). PD-1 Blockade-Induced DKK1 Expression by CD8+ T Cells Promotes Blood-Brain Barrier Permeabilization. Cancer discovery, 16(5), 976-992. https://
BibTeX
@article{deo2026pd,
author = {Deo, Abhilash and Levin, Sapir and Buxbaum, Chen and Benguigui, Madeleine and Manobla, Bar and Saar, Galit and Bosak, Noam and Bergmann, Eyal and Eran, Ayelet and Grinfeld, Anat and Harel, Michal and Lahav, Coren and Raviv, Ziv and Daher, Sameh and Zer, Alona and Reuter, Julia Helena and Heuβel, Claus Peter and Christopoulos, Petros and Yizhak, Keren and Shaked, Yuval},
title = {{PD-1 Blockade-Induced DKK1 Expression by CD8+ T Cells Promotes Blood-Brain Barrier Permeabilization}},
journal = {Cancer discovery},
year = {2026},
month = may,
volume = {16},
number = {5},
pages = {976--992},
publisher = {American Association for Cancer Research},
issn = {2159-8274},
doi = {10.1158/
url = {https://
pmid = {41525686},
pmcid = {PMC13133603}
}
RIS
TY - JOUR
AU - Deo, Abhilash
AU - Levin, Sapir
AU - Buxbaum, Chen
AU - Benguigui, Madeleine
AU - Manobla, Bar
AU - Saar, Galit
AU - Bosak, Noam
AU - Bergmann, Eyal
AU - Eran, Ayelet
AU - Grinfeld, Anat
AU - Harel, Michal
AU - Lahav, Coren
AU - Raviv, Ziv
AU - Daher, Sameh
AU - Zer, Alona
AU - Reuter, Julia Helena
AU - Heuβel, Claus Peter
AU - Christopoulos, Petros
AU - Yizhak, Keren
AU - Shaked, Yuval
TI - PD-1 Blockade-Induced DKK1 Expression by CD8+ T Cells Promotes Blood-Brain Barrier Permeabilization
T2 - Cancer discovery
J2 - Cancer Discov
PY - 2026
DA - 2026/
VL - 16
IS - 5
SP - 976
EP - 992
SN - 2159-8274
PB - American Association for Cancer Research
DO - 10.1158/
UR - https://
LA - en
ER -
CSL-JSON
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