Myeloid Cell Classification and Therapeutic Opportunities Within the Glioblastoma Tumor Microenvironment in the Single Cell-Omics Era

Larkin, Collin J.; Arrieta, Víctor A.; Najem, Hinda; Li, Gongbo; Zhang, Peng; Miska, Jason; Chen, Peiwen; James, C. David; Sonabend, Adam M.; Heimberger, Amy B.

doi:10.3389/fimmu.2022.907605

Cited by 6 publications

(11 citation statements)

References 62 publications

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“…Recent immunophenotyping studies have revealed that the glioma TIME is characterized by a heterogeneous, predominantly myeloid population (Chen et al, 2017) (Larkin et al, 2022) (Gupta et al, 2022 Preprint). These myeloid cells include yolk sacderived brain resident microglia (MG), bone marrow-derived macrophages (MACs), and monocyte-derived macrophages (MDMs) (Morantz et al, 1979) (Gupta et al, 2022 Preprint).…”

Section: Introductionmentioning

confidence: 99%

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

Peshoff

Gupta

Trivedi

et al. 2023

Preprint

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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.

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Section: Introductionmentioning

confidence: 99%

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

Peshoff

Gupta

Trivedi

et al. 2023

Preprint

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“…Our IMC data, along with published single-cell sequencing studies, demonstrate that myeloid cells exist in a spectrum of activation states in GBM ( 7 , 18 ) with the polarization of myeloid cells toward either microglia or TAMs being the most prominent ( 22 , 28 , 29 ). However, the exact ontogeny of the identified myeloid populations in GBM remains unclear ( 4 ). We therefore used partition-based graph abstraction (PAGA) analysis to understand the relationships between the seven myeloid populations identified by IMC (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…As such, they are viewed as attractive targets for novel treatments for GBM, with preclinical data supporting the benefit of macrophage modulation (3). However, the myeloid cell compartment is extremely heterogeneous in GBM, being able to adopt a spectrum of proinflammatory and suppressive states (4,5) with immunosuppressive phenotypes being associated with worse outcome (6)(7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

“…Myeloid cells (which include monocytes, macrophages, and tissue resident microglial cells) are major components of GBM, constituting 30 to 40% of all cells found within the GBM tumor microenvironment (TME) ( 3 , 4 ). Myeloid cells are believed to play major roles in promoting GBM progression and treatment resistance, including impairing response to radiotherapy and immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

“…At present, we have limited knowledge of where the different myeloid cell populations compartmentalize in the complex TME of GBMs, and what tissue factors may shape their positioning and differentiation. This is partly due to the limitations of bulk-based or cell suspension–based methods for studying the GBM TME, which cannot simultaneously capture the spatial and phenotypic heterogeneities seen in myeloid cells in GBM ( 4 ). Spatial heterogeneity arises in GBM due to variation in the degree of tumor cell infiltration into healthy tissue and due to emergence of hallmark features of GBM such as hypoxia-induced necrosis and microvascular proliferation that differentiate it from lower-grade tumors ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

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Hypoxia coordinates the spatial landscape of myeloid cells within glioblastoma to affect survival

Haley,

Bere,

Minshull

et al. 2024

Sci. Adv.

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Myeloid cells are highly prevalent in glioblastoma (GBM), existing in a spectrum of phenotypic and activation states. We now have limited knowledge of the tumor microenvironment (TME) determinants that influence the localization and the functions of the diverse myeloid cell populations in GBM. Here, we have utilized orthogonal imaging mass cytometry with single-cell and spatial transcriptomic approaches to identify and map the various myeloid populations in the human GBM tumor microenvironment (TME). Our results show that different myeloid populations have distinct and reproducible compartmentalization patterns in the GBM TME that is driven by tissue hypoxia, regional chemokine signaling, and varied homotypic and heterotypic cellular interactions. We subsequently identified specific tumor subregions in GBM, based on composition of identified myeloid cell populations, that were linked to patient survival. Our results provide insight into the spatial organization of myeloid cell subpopulations in GBM, and how this is predictive of clinical outcome.

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

Peshoff,

Gupta,

Oberai

et al. 2024

Neuro-Oncology

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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 anti-tumor 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 two 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 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.

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Myeloid Cell Classification and Therapeutic Opportunities Within the Glioblastoma Tumor Microenvironment in the Single Cell-Omics Era

Cited by 6 publications

References 62 publications

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

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

Hypoxia coordinates the spatial landscape of myeloid cells within glioblastoma to affect survival

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

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