TREM2 promotes glioma progression and angiogenesis mediated by microglia/brain macrophages

Triggering receptor expressed on myeloid cell 2 (TREM2), a myeloid cell-specific signaling molecule, controls essential functions of microglia and impacts on the pathogenesis of Alzheimer's disease and other neurodegenerative disorders. TREM2 is also highly expressed in tumor-associated macrophages in different types of cancer. Here, we studied whether TREM2 influences glioma progression. We found a gender-dependent effect of glioma growth in wild-type (WT) animals injected with GL261-EGFP glioma cells. Most importantly, TREM2 promotes glioma progression in male but not female animals. The accumulation of glioma-associated microglia/macrophages (GAMs) and CD31⁺ blood vessel density is reduced in male TREM2-deficient mice. A transcriptomic analysis of glioma tissue revealed that TREM2 deficiency suppresses immune-related genes. In an organotypic slice model devoid of functional vascularization and immune components from periphery, the tumor size was not affected by TREM2-deficiency. In human resection samples from glioblastoma, TREM2 is upregulated in GAMs. Based on the Cancer Genome Atlas Program (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases, the TREM2 expression levels were negatively correlated with survival. Thus, the TREM2-dependent crosstalk between GAMs and the vasculature formation promotes glioma growth.