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

BACKGROUND: Glioblastomas (GBMs) are central nervous system tumors that resist standard-of-care interventions and even immune checkpoint blockade. Myeloid cells in the tumor microenvironment can contribute to GBM progression; therefore, emerging immunotherapeutic approaches include reprogramming these cells to achieve desirable antitumor activity. Triggering receptor expressed on myeloid cells 2 (TREM2) is a myeloid signaling regulator that has been implicated in a variety of cancers and neurological diseases with contrasting functions, but its role in GBM immunopathology and progression is still under investigation. METHODS: Our reverse translational investigations leveraged single-cell RNA sequencing and cytometry of human gliomas to characterize TREM2 expression across myeloid subpopulations. Using 2 distinct murine glioma models, we examined the role of Trem2 on tumor progression and immune modulation of myeloid cells. Furthermore, we designed a method of tracking phagocytosis of glioma cells in vivo and employed in vitro assays to mechanistically understand the influence of TREM2 signaling on tumor uptake. RESULTS: We discovered that TREM2 expression does not correlate with immunosuppressive pathways, but rather showed strong a positive association with the canonical phagocytosis markers lysozyme (LYZ) and macrophage scavenger receptor (CD163) in gliomas. While Trem2 deficiency was found to be dispensable for gliomagenesis, Trem2+ myeloid cells display enhanced tumor uptake compared to Trem2- cells. Mechanistically, we demonstrate that TREM2 mediates phagocytosis via Syk signaling. CONCLUSIONS: These results indicate that TREM2 is not associated with immunosuppression in gliomas. Instead, TREM2 is an important regulator of phagocytosis that may be exploited as a potential therapeutic strategy for brain tumors.

Immune landscape of isocitrate dehydrogenase-stratified primary and recurrent human gliomas.

BACKGROUND: Human gliomas are classified using isocitrate dehydrogenase (IDH) status as a prognosticator; however, the influence of genetic differences and treatment effects on ensuing immunity remains unclear. METHODS: In this study, we used sequential single-cell transcriptomics on 144,678 and spectral cytometry on over two million immune cells encompassing 48 human gliomas to decipher their immune landscape. RESULTS: We identified 22 distinct immune cell types that contribute to glioma immunity. Specifically, brain-resident microglia (MG) were reduced with a concomitant increase in CD8+ T lymphocytes during glioma recurrence independent of IDH status. In contrast, IDH-wild-type-associated patterns, such as an abundance of antigen-presenting cell-like MG and cytotoxic CD8+ T cells, were observed. Beyond elucidating the differences in IDH, relapse, and treatment-associated immunity, we discovered novel inflammatory MG subpopulations expressing granulysin, a cytotoxic peptide, which is otherwise expressed in lymphocytes only. Furthermore, we provide a robust genomic framework for defining macrophage polarization beyond M1/M2 paradigm and reference signatures of glioma-specific tumor immune microenvironment (termed Glio-TIME-36) for deconvoluting transcriptomic datasets. CONCLUSIONS: This study provides advanced optics of the human pan-glioma immune contexture as a valuable guide for translational and clinical applications.

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

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.