Deficiency of SMARCB1 drives an immunosuppressive microenvironment in meningioma.

Meningiomas are the most common primary intracranial tumor in adults and systemic therapy is urgently needed for high-grade fatal tumors and those cannot be completely removed by surgery. Multiomics studies have established a molecular classification system in addition to the grading system by the World Health Organization, and SWI/SNF-related BAF chromatin remodeling complex subunit B1 (SMARCB1) mutation was enriched in the immunogenic subgroup. Meningiomas are myeloid-dominant tumors with abundant and unevenly distributed CD163+ macrophages, a feature linked to intratumoral heterogeneity. However, the biological drivers of this phenomenon remain unknown. A study cohort consisting of 113 patients was established to examine the association between serum immune profile and relapse-free survival. The second study cohort containing 35 patients across different WHO grades and disease states was established to validate and identify immune cell infiltration in the tumor microenvironment. Spatial distribution of immune cells was accessed by immunohistochemistry staining and multiplex immunofluorescence staining. Single-cell RNA sequencing (RNA-seq), bulk RNA-seq and whole exon seq data were analyzed to identify genomic signatures that represent the immunogenic subgroup of meningiomas. Public databases were explored to determine a potential mechanistic link between SMARCB1 and the interleukin-17/colony stimulating factor 1 (IL-17/CSF1) axis. Serum IL-17 A and IL-5 levels favored a good prognosis of meningioma. CD163+ macrophages were enriched in meningiomas regardless of the WHO grade and disease status (primary or recurrent). Compared to CD25+/Foxp3+ regulatory T cells and CD15+/CD33+ myeloid-derived suppressor cells, CD163+ macrophages tend to be more enriched around SMARCB1-deficient tumor cells. RNA-seq revealed that a 14-gene signature, including IL-17, CSF1, and related upstream and downstream genes, accurately characterizes the immunogenic subtype of meningiomas. The findings reveal that the infiltration of CD163+ macrophages in meningioma may be mediated by the IL-17/CSF1 axis through SMARCB1 regulation.