Tmic-29. Characterizing the Role of Triggering Receptor Expressed on Myeloid Cells 2 (Trem2)-Expressing Microglia/Macrophages in Glioblastoma

Abstract

The tumor microenvironment in glioblastoma (GBM) contains numerous cell types, notably a rich immune compartment dominated by myeloid cells, such as brain-resident microglia and infiltrating macrophages. However, current immunotherapies target lymphoid components like T cells, which are sparse in the brain and the tumors originating there. Therefore, immune checkpoint drugs designed for systemic cancers have not yielded significant benefits for patients with glioblastoma, and the efficacy of immunotherapy for central nervous system malignancies lags behind treatments for other solid tumors. Further understanding of the myeloid compartment is necessary for developing glioblastoma immunotherapies. Our recent single cell RNA-seq (scRNA-seq) analyses have identified microglial clusters that are enriched for antigen presentation and phagocytic gene expression modules. These clusters were restricted to microglia and macrophages seen only in glioma patients, but not in myeloid cells derived from non-glioma brain controls. Triggering receptor expressed on myeloid cells 2 (TREM2), a receptor abundant on microglia and vital for the detection and phagocytosis of pathogens, was highly expressed in these clusters. Because microglia expressing TREM2 play a protective role in neurodegenerative diseases like Alzheimer's disease, we examined the function of TREM2+ myeloid cells in GBM using mice lacking TREM2. Implantation of GL261 cells in TREM2-/- mice showed significantly reduced survival relative to wild-type mice, suggesting a protective role of TREM2+ myeloid cells in glioma. Data on immunophenotyping of glioma xenografts from WT and TREM2-/- mice brains using state of the art technologies (e.g. Cytek) will be presented. We conclude that TREM2 is a phagocytic immunoregulator in glioblastoma, manifesting anti-glioma properties to TREM2+ myeloid cells.

Remote Neuroinflammation in Newly Diagnosed Glioblastoma Correlates with Unfavorable Clinical Outcome

“…A recent review on immunotherapy in glioblastoma (52) however suggested that exactly these inflammation-related tumors could be more responsive to immunomodulatory approaches such as immune checkpoint blockade (53) or modulation of novel immune targets e.g. TREM2 (54, 55). Taken together, our findings confirm that glioblastoma should be seen as a whole brain disease and might explain why local therapy approaches have to date not been able to achieve remarkable effects on patient survival.…”

Autophagy in glioblastoma: A mechanistic perspective

“…24 TREM2 regulates GBMs by modulating angiogenesis and phagocytosis. 25,26 Transmembrane protein 119 (TMEM119) has been identified as a promising marker for microglia. 27 It has been shown that TMEM119 can also be used as a marker for brain-metastasis-associated microglia.…”

“…TREM2 is highly expressed in macrophages and microglia in GBMs and high TREM2 expression correlates with poor survival and poor prognosis in patients with GBM 24 . TREM2 regulates GBMs by modulating angiogenesis and phagocytosis 25,26 . Transmembrane protein 119 (TMEM119) has been identified as a promising marker for microglia 27 .…”

HMGB1/TREM2 positive feedback loop drives the development of radioresistance and immune escape of glioblastoma by regulating TLR4/Akt signaling

“…Yan Y. et al found that TREM2 was highly overexpressed in glioma-associated macrophages, and inhibiting TREM2 in microglia suppressed the growth and angiogenesis activity of glioma cells [24]. Peshoff MM et al discovered that TREM2 was a vital regulator of phagocytosis in gliomas, compared with TREM2 − myeloid cells, TREM2 + cells displayed enhanced ability of tumor uptake [25]. However, whether the strategy of blocking TREM2 in GBM cells can turn the immunologically "cold" GBM into hot one and reverse the radioresistance of GBM cells, as well as the specific molecular mechanisms involved are still unclear now.…”