Targeting the TREM1-positive myeloid microenvironment in glioblastoma

Abstract

Background: Tumor cellular and molecular heterogeneity is a hallmark of glioblastoma and underlies treatment resistance and recurrence. This manuscript investigated the myeloid-derived microenvironment as a driver of glioblastoma heterogeneity and provided a pharmacological pathway for its suppression.

Methods: Transcriptomic signatures of glioblastoma infiltrated myeloid-derived cells were assessed using R2: genomic platform, Ivy Glioblastoma Spatial Atlas, and single-cell RNA-seq data of primary and recurrent glioblastomas. Myeloid-derived cell prints were evaluated in five PDX cell lines using RNA-seq data. Two immunocompetent mouse glioblastoma models were utilized to isolate and characterize tumor-infiltrated myeloid-derived cells and glioblastoma/host cell hybrids. The ability of an inhibitor of HuR dimerization SRI42127 to suppress TREM1⁺-microenvironment and glioblastoma/myeloid-derived cell interaction was assessed in vivo and in vitro.

Results: TREM1⁺-microenvironment is enriched in glioblastoma peri-necrotic zones. TREM1 appearance is enhanced with tumor grade and associated with poor patient outcomes. We confirmed an expression of a variety of myeloid-derived cell markers, including TREM1, in PDX cell lines. In mouse glioblastoma models, we demonstrated a reduction in the TREM1⁺-microenvironment and glioblastoma/host cell fusion after treatment with SRI42127. In vitro assays confirmed inhibition of cell fusion events and reduction of myeloid-derived cell migration towards glioblastoma cells by SRI42127 and TREM1 decoy peptide (LP17) versus control treatments.

Conclusions: TREM1⁺-myeloid-derived microenvironment promulgates glioblastoma heterogeneity and is a therapeutic target. Pharmacological inhibition of HuR dimerization leads to suppression of the TREM1⁺-myeloid-derived microenvironment and the neoplastic/non-neoplastic fusogenic cell network.

Keywords: glioblastoma; heterogeneity; microenvironment; peri-necrotic.