Elucidating the association between TLR-4 expression and the clinical course of glioblastoma leptomeningeal disease
Menée à l'aide de séries de données transcriptomiques, de données protéomiques, d'échantillons tumoraux, d'échantillons de liquides cérébrospinaux et d'un modèle murin, cette étude examine l'association entre l'expression du récepteur TLR-4 et l'évolution clinique d'une maladie leptoméningée liée à un glioblastome
Background : No treatment exists for leptomeningeal disease (LMD) occurring in a subset of glioblastoma (GBM) patients and portends to a very poor prognosis. This study investigated the association of the Toll-Like Receptor 4 (TLR-4) pro-inflammatory pathway in LMD secondary to GBM.
Methods : We interrogated relevant transcriptomic and proteomic datasets, and primary patient tissue and cerebrospinal fluid (CSF) specimens. To understand translational associations, we introduced a syngeneic murine model and assessed direct TLR-4 antagonism.
Results : TLR-4 was robustly overexpressed in glioma tumors, with a significant survival detriment in GBM specifically. Using single-cell RNA-sequencing, we demonstrated the CSF profile of LMD generally expressed high levels of TLR-4 and enrichment of macrophage immune profile compared to control. In patient specimens, the TLR-4 pathway was significantly expressed in tissue mRNA from GBM LMD (P = 0.020), and increased in CSF from GBM LMD patients compared to controls. TLR-4 antagonism demonstrated favorable anti-tumor effect in multiple GBM cell lines, and significant increase in overall survival in our murine model (median 24 versus 15 days, P = 0.002).
Conclusions : TLR-4 expression associates with GBM LMD. TLR-4 antagonism results in anti-cancer effect in vitro and prolonged survival in vivo making it a worthy candidate for further study.
British Journal of Cancer , résumé, 2025