Triggering receptor expressed on myeloid cells 2 (TREM2) regulates phagocytosis in glioblastoma

Abstract

Glioblastomas (GBMs) are tumors of the central nervous system that remain recalcitrant to both standard of care chemo-radiation and immunotherapies. Emerging approaches to treat GBMs include depletion or re-education of innate immune cells including microglia (MG) and macrophages (MACs). Here we show myeloid cell restricted expression of triggering receptor expressed on myeloid cells 2 (TREM2) across low- and high-grade human gliomas. TREM2 expression did not correlate with immunosuppressive pathways, but rather showed strong positive association with phagocytosis markers such as lysozyme (LYZ) and CD163 in gliomas. In line with these observations in patient tumors, Trem2-/- mice did not exhibit improved survival compared to wildtype (WT) mice when implanted with mouse glioma cell lines, unlike observations previously seen in peripheral tumor models. Gene expression profiling revealed pathways related to inflammation, adaptive immunity, and autophagy that were significantly downregulated in tumors from Trem2-/- mice compared to WT tumors. Using ZsGreen-expressing CT-2A orthotopic implants, we found higher tumor antigen engulfment in Trem2+ MACs, MG, and dendritic cells. Our data uncover TREM2 as an important immunomodulator in gliomas and inducing TREM2 mediated phagocytosis can be a potential immunotherapeutic strategy for brain tumors. Key pointsO_LITREM2 is not associated with immunosuppressive molecules in GBM C_LIO_LITREM2 is associated with phagocytosis in both human and mouse gliomas C_LIO_LIDeletion of Trem2 in mice does not improve survival in glioma models C_LI Importance of the studyTriggering receptor expressed on myeloid cells 2 (TREM2) has been implicated as a major immunoregulator in both neurodegenerative diseases and systemic cancers, yet its functional role in gliomas remains unclear. This study reveals that unlike in other cancers, TREM2 is not associated with immunosuppression in the glioma microenvironment. In fact, TREM2 expression is associated with phagocytosis in both human and mouse gliomas, similar to its role in Alzheimers disease. These findings indicate that TREM2 blockade will not be a viable treatment strategy for gliomas. Instead, TREM2 induction may boost the potential of myeloid cells in the tumor microenvironment to engulf cancer cells.