TREM2 inhibition triggers anti-tumor cell activity of myeloid cells in glioblastoma [scRNA]

The prevailing view is that myeloid cells in the tumor microenvironment (TME) are immunosuppressive and promote glioblastoma (GBM) progression. However, myeloid cells have the functional plasticity to restrict or support tumor cell growth. TREM2 plays important roles in brain microglial function in neurodegenerative diseases, but the role of TREM2 in the GBM TME has not been examined. We found TREM2 is highly expressed in myeloid subsets, including macrophages and microglia in human and mouse GBM tumors and that high TREM2 expression correlates with poor prognosis in GBM patients. TREM2 loss of function in human macrophages and mouse myeloid cells increased tumoricidal capacity. TREM2 in myeloid cells restricts IFNγ-induced immunoactivation and proinflammatory polarization. In orthotopic mouse GBM models, Trem2-/- mice and mice with acute brain Trem2 reduction demonstrate survival benefit. Trem2 inhibition reprograms myeloid phenotypes and increases PD-1+CD8+ T cells in the TME. Trem2 deficiency enhances the effectiveness of anti-PD-1 treatment and may represent a therapeutic strategy for GBM patients. Bone marrow-derived macrophages (BMDMs) were isolated and differentiated from trem2 transgenic mice, Trem2+/+ (n=2), Trem2-/- (n=2). Cells were treated with PBS (n=2), 10 ng/mL IFNγ (n=2), 100 ng/mL LPS (n=2), or dead SB28 tumor cells (n=2) for 6 hours. Total RNA from each sample/genotype was isolated and sequenced. Primary microglia were enriched from brain cortex of postnatal day 2 Trem2+/+ mouse pups (n=12). Primary microglia were treated with Trem2-lowering antisense oligonucleotide (ASO) or inactive ASO for 72 hours. Trem2 ASO (n=2), inactive (n=2). Cells were then treated with PBS (n=2),10 ng/mL IFNγ (n=2) or dead SB28 tumor cells (n=2) for 6 hours. Total RNA from each sample/treatment was isolated and sequenced. Trem2+/+ mice were intracerebroventricularly injected with 400 μg (10ul) Trem2 ASO (n=5) or inactive ASO (n=5). 7 days later, all mice were intracerebrally injected with SB28 cells. 30 days later, SB28 glioblastoma were dissected from ASO-treated mice brain and dissociated into single-cell suspensions for RNA-seq. Trem2 ASO (n=2), inactive ASO (n=2).