Distinct roles of TREM2 in central nervous system cancers and peripheral cancers

Area of Science:

• Neuro-oncology
• Immunology
• Cancer Biology

Background:

• Glioblastomas (GBM) are aggressive brain cancers with significant myeloid cell infiltration.
• Therapeutic targets in peripheral cancers may not translate to the central nervous system (CNS) environment.
• The role of triggering receptor expressed on myeloid cells-2 (TREM2) in CNS cancers is not well understood.

Purpose of the Study:

• To investigate the function of TREM2 in glioblastoma.
• To determine if TREM2 is a viable therapeutic target for GBM.
• To explore the relationship between TREM2 expression and patient survival.

Main Methods:

• Single-cell and spatial sequencing of GBM tumors.
• In vivo studies using genetic and pharmacological TREM2 manipulation.
• Analysis of TREM2 expression in relation to myeloid and T cell signatures.
• Investigation of CNS-enriched sphingolipids binding to TREM2.
• Correlation of TREM2 expression with clinical outcomes.
• Adeno-associated virus-mediated TREM2 overexpression studies.

Main Results:

• TREM2 is downregulated in GBM-infiltrated myeloid cells.
• TREM2 deficiency promotes GBM progression in vivo.
• Reduced TREM2 expression correlates with immunosuppressive myeloid and T cell exhaustion signatures.
• CNS-enriched sphingolipids activate TREM2 on myeloid cells, eliciting antitumor responses.
• High TREM2 expression in myeloid cells is associated with better GBM patient survival.
• TREM2 overexpression impedes GBM progression and synergizes with anti-PD-1 therapy.

Conclusions:

• TREM2 plays an immunoprotective role in glioblastoma, contrasting its role in peripheral cancers.
• Targeting TREM2 offers a potential therapeutic strategy for GBM.
• These findings highlight the importance of organ-specific approaches in myeloid cell-directed cancer immunotherapy.