IMMU-28. TREM2 INHIBITION REPROGRAMS MYELOID CELLS TO STIMULATE ANTI-TUMOR IMMUNITY THROUGH BOTH DIRECT AND INDIRECT MECHANISMS

Abstract

Abstract The prevailing view is that myeloid cells—macrophages and microglia—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 functional role of TREM2 in the GBM TME and whether TREM2 represents a meaningful therapeutic target remain largely unknown. To address these questions, we investigated the immune and tumor cell consequences of TREM2 inhibition by multiple orthogonal approaches—transgenic mice, antisense oligonucleotides, and blocking antibodies—in immunocompetent preclinical models (SB28, NPA C54B) and human GBM samples through bulk and single cell RNA-sequencing, flow cytometry, biochemistry, and functional assays. 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 IFNγ-induced immunoactivation and proinflammatory polarization. Conditioned media from TREM2 deficient human macrophages directly killed patient-derived GBM tumor cells, and biochemical analysis identified TNF and other putative tumoricidal proteins in this conditioned media. In mouse GBM models, mice with chronic and acute Trem2 loss of function demonstrated increased tumor cell death and increased animal survival. Trem2 inhibition reprogrammed myeloid cell phenotypes and increased PD-1+CD8+ T cells in the TME. Remarkably, Trem2 deficiency enhanced the effectiveness of anti-PD-1 treatment in vivo. Trem2 inhibition suppresses tumor cell growth through direct and indirect immune cell mechanisms--by reshaping myeloid subset and T cell functions. Thus, Trem2 inhibitory strategies, in combination with immune checkpoint blockade, may represent an attractive new approach for GBM therapy.