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PD-1 blockade-induced DKK1 expression by CD8+ T cells promotes blood-brain barrier permeabilization

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...

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Main Authors: Deo, Abhilash (Author) , Levin, Sapir (Author) , Buxbaum, Chen (Author) , Benguigui, Madeleine (Author) , Manobla, Bar (Author) , Saar, Galit (Author) , Bosak, Noam (Author) , Bergmann, Eyal (Author) , Eran, Ayelet (Author) , Grinfeld, Anat (Author) , Harel, Michal (Author) , Lahav, Coren (Author) , Raviv, Ziv (Author) , Daher, Sameh (Author) , Zer, Alona (Author) , Reuter, Julia (Author) , Heußel, Claus Peter (Author) , Christopoulos, Petros (Author) , Yizhak, Keren (Author) , Shaked, Yuval (Author)
Format: Article (Journal)
Language:English
Published: May 2026
In: Cancer discovery
Year: 2026, Volume: 16, Issue: 5, Pages: 976-992
ISSN:2159-8290
DOI:10.1158/2159-8290.CD-25-1222
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1158/2159-8290.CD-25-1222
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Author Notes:Abhilash Deo, Sapir Levin, Chen Buxbaum, Madeleine Benguigui, Bar Manobla, Galit Saar, Noam Bosak, Eyal Bergmann, Ayelet Eran, Anat Grinfeld, Michal Harel, Coren Lahav, Ziv Raviv, Sameh Daher, Alona Zer, Julia Helena Reuter, Claus Peter Heuβel, Petros Christopoulos, Keren Yizhak, and Yuval Shaked
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Summary: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/TCF and FOXM1 pathways, contributing to endothelial cell destabilization. Depleting plasma DKK1 restored BBB integrity and reduced experimental BrM formation. Clinically, patients with lung cancer receiving anti-PD-1 exhibited increased magnetic resonance imaging contrast enhancement in the brain, suggestive of BBB perturbations, and increasing plasma DKK1 levels correlated with higher BrM incidence in nonresponders. Sequential administration of anti-PD-1 followed by cisplatin improved intracranial cisplatin delivery and therapeutic efficacy in ICI-resistant BrM. These findings identify anti-PD-1-induced BBB modulation as a tractable vulnerability in BrM management.
Item Description:Veröffentlicht: 1. Mai 2026
Gesehen am 13.08.2026
Im Titel ist das Pluszeichen hochgestellt
Physical Description:Online Resource
ISSN:2159-8290
DOI:10.1158/2159-8290.CD-25-1222

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