TREM2 inhibition triggers antitumor cell activity of myeloid cells in glioblastoma.
Rui SunRowland H HanColin McCornackSaad M KhanG Travis TaborYun ChenJinchao HouHaowu JiangKathleen M SchochDiane D MaoRyan ClearyAlicia YangQin LiuJingqin R LuoAllegra A PettiTimothy M MillerJason D UlrichDavid M HoltzmanAlbert H KimPublished in: Science advances (2023)
Triggering receptor expressed on myeloid cells 2 (TREM2) plays important roles in brain microglial function in neurodegenerative diseases, but the role of TREM2 in the GBM TME has not been examined. Here, we found that 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 patients with GBM. TREM2 loss of function in human macrophages and mouse myeloid cells increased interferon-γ-induced immunoactivation, proinflammatory polarization, and tumoricidal capacity. In orthotopic mouse GBM models, mice with chronic and acute Trem2 loss of function exhibited decreased tumor growth and increased survival. Trem2 inhibition reprogrammed myeloid phenotypes and increased programmed cell death protein 1 (PD-1) + CD8 + T cells in the TME. Last, Trem2 deficiency enhanced the effectiveness of anti-PD-1 treatment, which may represent a therapeutic strategy for patients with GBM.
Keyphrases
- poor prognosis
- induced apoptosis
- dendritic cells
- bone marrow
- acute myeloid leukemia
- cell cycle arrest
- endothelial cells
- long non coding rna
- randomized controlled trial
- inflammatory response
- type diabetes
- stem cells
- cell death
- intensive care unit
- signaling pathway
- induced pluripotent stem cells
- binding protein
- functional connectivity
- replacement therapy
- cell proliferation
- diabetic rats
- single cell
- resting state
- peripheral blood
- lipopolysaccharide induced
- cerebral ischemia