OSCR

Distinct immune landscapes characterize highly versus minimally invasive brain metastases.

Overview

Authors: Sarah M Maritan1,2, Elham Karimi1, Matthew Dankner1,2, Aldo Hernandez-Corchado3,4, Miranda W Yu1,5, Matthew G Annis1, Yashar Aghazadeh Habashi1, Morteza Rezanejad1, Bridget Liu1, Nebras Koudieh6, Emilie Pichette7, Parvaneh Fallah8,9, Benoit Fiset1, Yuhong Wei1, Ali Nehme4, Chun Geun Lee10, Jack A Elias11, Morag Park1,12, Yasser Riazalhosseini3,4, Hamed Najafabadi3,4, Kevin Petrecca13,14, Marie-Christine Guiot7,13, Daniela F Quail1,5, Logan A Walsh1,3, Peter M Siegel1,2
ORCID iDs: Elham Karimi, Yashar Aghazadeh Habashi, Jack A Elias, Morag Park
14 affiliations
  1. Goodman Cancer Institute
  2. Department of Medicine, Division of Experimental Medicine
  3. Department of Human Genetics, Faculty of Medicine and Health Sciences
  4. Victor Phillip Dahdaleh Institute of Genomic Medicine, and
  5. Department of Physiology, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada
  6. Research Institute of McGill University Health Centre, Montreal, Quebec, Canada
  7. Department of Pathology, Faculty of Medicine and Health Sciences, and
  8. Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada
  9. Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada
  10. Intercollege, Hanyang University, Seoul, Korea
  11. Division of Medicine and Biological Sciences, Brown University, Providence, Rhode Island, USA
  12. Department of Oncology, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada
  13. Montreal Neurological Institute-Hospital, McGill University Health Centre, Montreal, Quebec, Canada
  14. Department of Neurology and Neurosurgery, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada
Institutions: McGill University (Canada); McGill University Health Centre (Canada); Research Institute of the McGill University Health Centre (Canada); Jewish General Hospital (Canada); Hanyang University (South Korea); Brown University (United States); Montreal Neurological Institute and Hospital (Canada)
Journal: JCI insight, volume 11, issue 10, article e199498
Dates: received 25 August 2025; accepted 31 March 2026; published online 22 May 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1172/jci.insight.199498 · PMID 42171608 · PMCID PMC13232719 · OpenAlex W7161976718
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: genetics / omics (modality), human (organism), mouse (organism), other condition (population), clinical / translational (subfield)
Methods: Statistics, Machine learning, fMRI & imaging
Keywords: Immunology, Oncology, Brain cancer
MeSH: Brain Neoplasms*, Chitinase-3-Like Protein 1*, Animals, Biomarkers, Tumor, CD8-Positive T-Lymphocytes, Female, Granzymes, Humans, Immune Checkpoint Inhibitors, Male, Mice, Proteomics, Tumor Microenvironment (* major topic)
Topic: Brain Metastases and Treatment (Pulmonary and Respiratory Medicine, Medicine), according to OpenAlex
Funding: Canadian Institutes of Health Research (CIHR PJT-175066)
Citations: cited by 1 paper (Europe PMC); 73 references in the paper

Abstract

Brain metastases (BrMs) occur in approximately 30% of cancer patients, causing nearly one-fifth of cancer deaths. While immune checkpoint inhibitors (ICIs) benefit some BrM patients, responses remain highly variable. This variability partly reflects distinct histopathological growth patterns that include minimally invasive (MI) and highly invasive (HI) brain BrMs. Here we show that MI BrMs exhibit robust immune infiltration, whereas HI lesions are immunosuppressed. However, histological differentiation between MI and HI can be challenging because of subjective margin assessment. Here, using highly multiplexed spatial proteomics on 119 tumor sections from 46 patients with BrMs, we identify CHI3L1 as a key mediator of the immunosuppressive microenvironment in HI BrMs. In preclinical models, genetic deletion of CHI3L1 converts immune-cold metastases into lymphocyte-rich, ICI-responsive lesions infiltrated by granzyme B+ CD8+ T cells. In BrM patients treated with ICI, immunohistochemical quantification of CHI3L1 expression was a stronger predictor of ICI response than traditional MI/HI classification. Thus, CHI3L1 represents a promising biomarker and therapeutic target for BrMs.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

The paper's code and data availability statement is in the Data section.

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Data

Datasets cited

Data availability

Values for all data points in graphs are reported in the Supporting Data Values file. The code for the NanoString GeoMx Digital Spatial Profiling analysis, including target matrix processing, differential expression analysis, and GSEA, is available at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE303531

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 2, 28 September 2026

  • Authors: added Jack A Elias (0000-0002-3124-8557); Morag Park (0000-0001-5400-606X); removed Jack A Elias; Morag Park
  • Funding: added Canadian Institutes of Health Research: CIHR PJT-175066

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 25 authors, 3 keywords, 13 MeSH terms, 73 references.

Cite

This paper

Maritan, S. M., Karimi, E., Dankner, M., Hernandez-Corchado, A., Yu, M. W., Annis, M. G., Aghazadeh Habashi, Y., Rezanejad, M., Liu, B., Koudieh, N., Pichette, E., Fallah, P., Fiset, B., Wei, Y., Nehme, A., Lee, C. G., Elias, J. A., Park, M., Riazalhosseini, Y., . . . Siegel, P. M. (2026). Distinct immune landscapes characterize highly versus minimally invasive brain metastases. JCI insight, 11(10), e199498. https://doi.org/10.1172/jci.insight.199498

BibTeX

@article{maritan2026distinct,
author = {Maritan, Sarah M and Karimi, Elham and Dankner, Matthew and Hernandez-Corchado, Aldo and Yu, Miranda W and Annis, Matthew G and Aghazadeh Habashi, Yashar and Rezanejad, Morteza and Liu, Bridget and Koudieh, Nebras and Pichette, Emilie and Fallah, Parvaneh and Fiset, Benoit and Wei, Yuhong and Nehme, Ali and Lee, Chun Geun and Elias, Jack A and Park, Morag and Riazalhosseini, Yasser and Najafabadi, Hamed and Petrecca, Kevin and Guiot, Marie-Christine and Quail, Daniela F and Walsh, Logan A and Siegel, Peter M},
title = {{Distinct immune landscapes characterize highly versus minimally invasive brain metastases}},
journal = {JCI insight},
year = {2026},
month = may,
volume = {11},
number = {10},
pages = {e199498},
publisher = {American Society for Clinical Investigation},
issn = {2379-3708},
doi = {10.1172/jci.insight.199498},
url = {https://doi.org/10.1172/jci.insight.199498},
pmid = {42171608},
pmcid = {PMC13232719}
}

RIS

TY - JOUR
AU - Maritan, Sarah M
AU - Karimi, Elham
AU - Dankner, Matthew
AU - Hernandez-Corchado, Aldo
AU - Yu, Miranda W
AU - Annis, Matthew G
AU - Aghazadeh Habashi, Yashar
AU - Rezanejad, Morteza
AU - Liu, Bridget
AU - Koudieh, Nebras
AU - Pichette, Emilie
AU - Fallah, Parvaneh
AU - Fiset, Benoit
AU - Wei, Yuhong
AU - Nehme, Ali
AU - Lee, Chun Geun
AU - Elias, Jack A
AU - Park, Morag
AU - Riazalhosseini, Yasser
AU - Najafabadi, Hamed
AU - Petrecca, Kevin
AU - Guiot, Marie-Christine
AU - Quail, Daniela F
AU - Walsh, Logan A
AU - Siegel, Peter M
TI - Distinct immune landscapes characterize highly versus minimally invasive brain metastases
T2 - JCI insight
J2 - JCI Insight
PY - 2026
DA - 2026/05/22
VL - 11
IS - 10
SP - e199498
SN - 2379-3708
PB - American Society for Clinical Investigation
DO - 10.1172/jci.insight.199498
UR - https://doi.org/10.1172/jci.insight.199498
LA - en
ER -

CSL-JSON

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