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

Abstract

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.

KR158 Spheres Harboring Slow-Cycling Cells Recapitulate High-Grade Glioma Features in an Immunocompetent System

“…GL261 is one of the most predominantly used preclinical models for high-grade glioma [ 42 , 43 , 44 ]. However, allograft tumors generated by this model exhibit features including low clonotypic diversity and high antigenicity, contrasting with human GBM [ 45 ].…”

TREM2 promotes macrophage polarization from M1 to M2 and suppresses osteoarthritis through the NF-κB/CXCL3 axis

“…TREM2 participates in clearing apoptotic cells and shows an anti-inflammatory effect, such as microglia and macrophages that promote anti-inflammatory gene expression in a TREM2-dependent manner 48 , 49 . TREM2 signaling promotes macrophage survival when growth factors are depleted in the extracellular environment, and it can also improve macrophage survival in stressful environments such as tissue damage and inflammation in vivo 50 . This study indicates that TREM2 alleviates cartilage injury and synovitis in OA mice.…”

Mechanisms of TREM2 mediated immunosuppression and regulation of cancer progression

“…Inhibiting the TREM2 gene can trigger the anti-tumor activity of GBM myeloid cells, increase interferon-γ induced immune activation, and promote pro-inflammatory phenotypes, ultimately inhibiting tumor growth and prolonging survival ( 22 ). In addition, TREM2 was found to be highly expressed in glioma-associated microglia/macrophages (GAMs) in glioma tissues and had a negative correlation with patient survival time ( 67 ). However, interestingly, TREM2 gene deficiency can, on one hand, inhibit genes in MHC I and II clusters (MHC I cluster: H2-D1, H2-M3, H2-Q4, etc.…”

“…However, interestingly, TREM2 gene deficiency can, on one hand, inhibit genes in MHC I and II clusters (MHC I cluster: H2-D1, H2-M3, H2-Q4, etc. ; MHC II cluster: H2-Ab1, H2-DMb1, H2-Eb1), inhibit antigen presentation, which in turn may lead to immune escape and impaired function of CD4 + /CD8 + cells and NK cells, and on the other hand, TREM2 gene deficiency can also inhibit the expression of immune genes with pro-angiogenic functions, such as Ccl5, Ccr5, Ccl12, Icam1, and Itgal, in glioma tissues, thereby inhibiting angiogenesis in glioma tissues and suppressing tumor growth and progression ( 67 ).…”