Spatial Transcriptomics Reveals a T Cell-Mediated Microglial Activation Axis of Immune Checkpoint Inhibition-Related Adverse Events in the Brain.
Overview
- Department of Anatomy & Neurobiology, School of Medicine University of California Irvine USA
- Department of Physiology & Biophysics School of Medicine University of California Irvine USA
- Department of Hematology and Oncology Freiburg University Medical Center Germany
- Department of Radiation Oncology School of Medicine University of California Irvine USA
Abstract
Immune checkpoint inhibitors (ICIs) targeting CTLA‐4 and PD‐1 have transformed cancer therapy, yet their immune‐related adverse events (irAEs) in various tissues, including the brain, remain poorly defined. ICI perturbs hippocampal‐dependent memory function by derailing neuro‐immune homeostasis and compromising synaptic integrity. However, the cellular and molecular mechanisms by which ICI alters regional interactions are not well understood. Using bulk RNA‐sequencing and MERFISH spatial transcriptomics in a syngeneic murine melanoma model, we show that ICI treatment remodels hippocampal gene expression and cellular organization. While tumor burden itself altered brain physiology, ICI distinctly modified the abundance and transcriptional states of neurons, microglia, astrocytes, oligodendrocytes, and T cells, with coordinated induction of inflammatory, synaptic, and immune‐response programs. Complementary analysis of human postmortem brain samples confirmed microglial activation as a key hallmark of ICI‐treated brains, highlighting the translational relevance of our findings. Finally, using a conditional deletion model, we show that T cells are indispensable for ICI‐driven microglial activation. Altogether, our results identify a T cell–microglia crosstalk axis as a driving mechanism of the pathophysiology of irAEs in the brain and provide a high‐resolution spatial model for better understanding neuroinflammatory responses during ICI‐induced unleashing of anti‐tumor immunity.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
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Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.The MERFISH data in this study were deposited in the Gene Expression Omnibus (GEO) repository under accession code GSE322277. The bulk RNA seq data were deposited in the GEO repository under accession number GSE322681.
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 1, 3 October 2026: the first record
Recorded: type, language, journal, pages, dates, 8 authors, 10 keywords, 2 funders, 65 references, 9 RRIDs.
Cite
This paper
Swami, D., El‐Khatib, S. M., Sureshchandra, S., Nguyen, E., Vinnakota, J. M., Zeiser, R., Othy, S., & Acharya, M. M. (2026). Spatial Transcriptomics Reveals a T Cell-Mediated Microglial Activation Axis of Immune Checkpoint Inhibition-Related Adverse Events in the Brain. Advanced science (Weinheim, Baden-Wurttemberg, Germany), e77733. https://
BibTeX
@article{swami2026spatia
author = {Swami, Devyani and El‐Khatib, Sanad M. and Sureshchandra, Suhas and Nguyen, Elise and Vinnakota, Janaki Manoja and Zeiser, Robert and Othy, Shivashankar and Acharya, Munjal M.},
title = {{Spatial Transcriptomics Reveals a T Cell-Mediated Microglial Activation Axis of Immune Checkpoint Inhibition-Related Adverse Events in the Brain}},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
year = {2026},
month = sep,
pages = {e77733},
publisher = {Wiley},
issn = {2198-3844},
doi = {10.1002/
url = {https://
pmid = {42813238},
pmcid = {PMC13624869}
}
RIS
TY - JOUR
AU - Swami, Devyani
AU - El‐Khatib, Sanad M.
AU - Sureshchandra, Suhas
AU - Nguyen, Elise
AU - Vinnakota, Janaki Manoja
AU - Zeiser, Robert
AU - Othy, Shivashankar
AU - Acharya, Munjal M.
TI - Spatial Transcriptomics Reveals a T Cell-Mediated Microglial Activation Axis of Immune Checkpoint Inhibition-Related Adverse Events in the Brain
T2 - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
J2 - Adv Sci (Weinh)
PY - 2026
DA - 2026/
SP - e77733
SN - 2198-3844
PB - Wiley
DO - 10.1002/
UR - https://
LA - en
ER -
CSL-JSON
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