Distinct immune landscapes characterize highly versus minimally invasive brain metastases
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.
Authors
- Parvaneh Fallah (ORCID: https://orcid.org/0000-0001-7885-2009)
- Daniela F. Quail (ORCID: https://orcid.org/0000-0002-6969-3250)
- Aldo Hernández-Corchado (ORCID: https://orcid.org/0000-0003-0682-3959)
- Kevin Petrecca (ORCID: https://orcid.org/0000-0002-8140-6402)
- Benoit Fiset (ORCID: https://orcid.org/0000-0003-0372-8868)
- Elham Karimi (ORCID: https://orcid.org/0000-0002-2204-0789)
- Ali Nehme (ORCID: https://orcid.org/0000-0001-5254-848X)
- Matthew G. Annis (ORCID: https://orcid.org/0000-0002-8776-004X)
- Yasser Riazalhosseini (ORCID: https://orcid.org/0000-0003-0875-618X)
- Sarah M. Maritan (ORCID: https://orcid.org/0000-0002-9703-7429)
- Logan A. Walsh (ORCID: https://orcid.org/0000-0001-8771-2577)
- Morteza Rezanejad (ORCID: https://orcid.org/0000-0001-8744-8534)
- Matthew Dankner (ORCID: https://orcid.org/0000-0003-4869-5895)
- Morag Park (ORCID: https://orcid.org/0000-0001-5400-606X)
- Nebras Koudieh
- Bridget Liu
- Chun Geun Lee
- Yashar Aghazadeh Habashi
- Jack A. Elias
- Hamed Najafabadi (ORCID: https://orcid.org/0000-0003-2735-4231)
- Miranda W. Yu
- Emilie Pichette
- Peter M. Siegel (ORCID: https://orcid.org/0000-0002-5568-6586)
- Marie-Christine Guiot
- Yuhong Wei
Institutions
- Montreal Neurological Institute and Hospital (CA)
- Brown University (US)
- Cancer Institute (WIA) (IN)
- McGill University Health Centre (CA)
- Jewish General Hospital (CA)
- Institute of Experimental Physics of the Slovak Academy of Sciences (SK)
- National Institute of Pathology (IN)
- Intercollege (CY)
- Goodman (Japan) (JP)
- Institute of Experimental Endocrinology of the Slovak Academy of Sciences (SK)
- Institute of Human Genetics (PL)
- Faculty of Public Health (GB)
- Czech Academy of Sciences, Institute of Experimental Medicine (CZ)
- Health and Human Development (2HD) Research Network (CM)
- Hanyang University (KR)
- McGill University (CA)
Publication Details
- Journal
- JCI Insight
- Published
- 2026-05-21
- DOI
- https://doi.org/10.1172/jci.insight.199498
- Primary Topic
- Brain Metastases and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Canadian Institutes of Health Research