TREM2 mediates MHCII-associated CD4<sup>+</sup>T cell response against gliomas

Zheng, Jiaying; Wang, Lingxiao; Zhao, Shouxun; Zhang, Wenjing; Chang, Yuzhou; Dheer, Aastha; Gao, Shan; Xu, Shengze; Ayasoufi, Katayoun; Al‐kharboosh, Rawan; Xie, Manling; Johnson, Aaron J.; Dong, Haidong; Quiñones‐Hinojosa, Alfredo

doi:10.1101/2023.04.05.535697

Cited by 4 publications

(2 citation statements)

References 57 publications

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“…Several very recent exciting, yet controversial studies have focused on the potential role of Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) in regulating phagocytosis in GBM [121,122]. TREM2 is expressed primarily on microglial cells and can be activated by a variety of ligands including bacteria, polyanionic molecules, lipoproteins and nucleic acids [123] TREM2 signals through DNAX Activator Proteins 10 and 12 (DAP10 and DAP12).…”

Section: Trem2mentioning

confidence: 99%

Phagocytosis Checkpoints in Glioblastoma: CD47 and Beyond

Afzal,

Bizink

et al. 2024

Preprint

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Glioblastoma multiforme (GBM) is one of the deadliest human cancers with very lim-ited treatment options available. The malignant behavior of GBM is manifest in a tu-mor which is highly invasive, resistant to standard cytotoxic chemotherapy and is strongly immunosuppressive. Immune checkpoint inhibitors have recently been in-troduced in the clinic and have yielded promising results in certain cancers. GBM however is largely refractory to these treatments. The immune checkpoint CD47 has recently gained attention as potential target for intervention as it conveys a “don’t eat me” signal to tumor associated macrophages via the inhibitory SIRP alpha protein. In preclinical models, administration of anti-CD47 monoclonal antibodies have shown impressive results with GBM and other tumor models. Several well characterized on-cogenic pathways have recently been shown to regulate CD47 expression in GBM cells and Glioma Stem cells (GSCs) include EGFR, beta catenin and LRIG2. Other macro-phage pathways involved in regulating phagocytosis including TREM2 and glycan binding proteins are discussed as well. Finally, Chimeric Antigen Receptor Macro-phages (CAR)-M could be leveraged for greatly enhancing phagocytosis of GBM and repolarization of the microenvironment in general. Here we comprehensively review the mechanisms that regulate about macrophage phagocytosis of GBM cells.

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Section: Trem2mentioning

confidence: 99%

Phagocytosis Checkpoints in Glioblastoma: CD47 and Beyond

Afzal,

Bizink

et al. 2024

Preprint

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“…In glioma, upregulated expression of trem2 in microglia creates an immunosuppressive environment that promotes tumor progression and implies a poor prognosis [12]. In addition, trem2 is also related to microglia-induced angiogenesis [13] and the recruitment and response of T cells [12,14,15]. Furthermore, downregulation of trem2 in glioma cells resulted in a significant growth-inhibitory effect [16].…”

Section: Introductionmentioning

confidence: 99%

Knockdown of trem2 promotes proinflammatory microglia and inhibits glioma progression via the JAK2/STAT3 and NF-κB pathways

Yan,

Bai,

Han

et al. 2024

Cell Commun Signal

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Background In the tumor immune microenvironment (TIME), triggering receptor expressed on myeloid cells 2 (trem2) is widely considered to be a crucial molecule on tumor-associated macrophages(TAMs). Multiple studies have shown that trem2 may function as an immune checkpoint in various malignant tumors, mediating tumor immune evasion. However, its specific molecular mechanisms, especially in glioma, remain elusive. Methods Lentivirus was transfected to establish cells with stable knockdown of trem2. A Transwell system was used for segregated coculture of glioma cells and microglia. Western blotting, quantitative real-time polymerase chain reaction (qRT‒PCR), and immunofluorescence (IF) were used to measure the expression levels of target proteins. The proliferation, invasion, and migration of cells were detected by colony formation, cell counting kit-8 (CCK8), 5-ethynyl-2’-deoxyuridine (EdU) and transwell assays. The cell cycle, apoptosis rate and reactive oxygen species (ROS) level of cells were assessed using flow cytometry assays. The comet assay and tube formation assay were used to detect DNA damage in glioma cells and angiogenesis activity, respectively. Gl261 cell lines and C57BL/6 mice were used to construct the glioma orthotopic transplantation tumor model. Results Trem2 was highly overexpressed in glioma TAMs. Knocking down trem2 in microglia suppressed the growth and angiogenesis activity of glioma cells in vivo and in vitro. Mechanistically, knockdown of trem2 in microglia promoted proinflammatory microglia and inhibited anti-inflammatory microglia by activating jak2/stat1 and inhibiting the NF-κB p50 signaling pathway. The proinflammatory microglia produced high concentrations of nitric oxide (NO) and high levels of the proinflammatory cytokines TNF-α, IL-6, and IL-1β, and caused further DNA damage and promoted the apoptosis rate of tumor cells. Conclusions Our findings revealed that trem2 in microglia plays a significant role in the TIME of gliomas. Knockdown of trem2 in microglia might help to improve the efficiency of inhibiting glioma growth and delaying tumor progression and provide new ideas for further treatment of glioma.

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Galectin-3 induces pathogenic immunosuppressive macrophages through interaction with TREM2 in lung cancer

Wang,

Wu,

Jiang

et al. 2024

J Exp Clin Cancer Res

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Background High infiltration of tumor-associated macrophages (TAMs) is associated with tumor promotion and immunosuppression. The triggering receptor expressed on myeloid cells 2 (TREM2) is emerged as a key immunosuppressive regulator for TAMs, however, how TREM2-expressing TAMs are recruited and what ligands TREM2 interacts with to mediate immunosuppression is unknown. Methods Flow cytometry and single-cell RNA sequencing were used to analyze TREM2 expression. Mechanistically, mass spectrometry and immunoprecipitation were employed to identify proteins binding to TREM2. Phagocytosis and co-culture experiments were used to explore the in vitro functions of galectin3-TREM2 pair. Establishment of TREM2f/f-Lyz2-cre mice to validate the role of TREM2 signaling pathway in lung carcinogenesis. GB1107 were further supplemented to validate the therapeutic effect of Galectin3 based on TREM2 signaling regulation. Results This study identified that abundant TREM2+ macrophages were recruited at the intra-tumor site through the CCL2-CCR2 chemotactic axis. Galectin-3 impaired TREM2-mediated phagocytosis and promoted the conversion of TREM2+ macrophages to immunosuppressive TAMs with attenuated antigen presentation and co-stimulatory functions both in vitro both in vivo, and galectin-3 is a potential ligand for TREM2. Genetic and pharmacological blockade of TREM2 and galectin-3 significantly inhibited lung cancer progression in subcutaneous and orthotopic cancer models by remodeling the tumor immune microenvironment. Conclusion Our findings revealed a previously unknown association between galectin-3 and TREM2 in TAMs of lung cancer, and suggested simultaneous inhibition of galectin3 and TREM2 as potent therapeutic approach for lung cancer therapy. Graphical Abstract

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TREM2 mediates MHCII-associated CD4⁺T cell response against gliomas

Cited by 4 publications

References 57 publications

Phagocytosis Checkpoints in Glioblastoma: CD47 and Beyond

Phagocytosis Checkpoints in Glioblastoma: CD47 and Beyond

Knockdown of trem2 promotes proinflammatory microglia and inhibits glioma progression via the JAK2/STAT3 and NF-κB pathways

Galectin-3 induces pathogenic immunosuppressive macrophages through interaction with TREM2 in lung cancer

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TREM2 mediates MHCII-associated CD4+T cell response against gliomas

Cited by 4 publications

References 57 publications

Phagocytosis Checkpoints in Glioblastoma: CD47 and Beyond

Phagocytosis Checkpoints in Glioblastoma: CD47 and Beyond

Knockdown of trem2 promotes proinflammatory microglia and inhibits glioma progression via the JAK2/STAT3 and NF-κB pathways

Galectin-3 induces pathogenic immunosuppressive macrophages through interaction with TREM2 in lung cancer

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TREM2 mediates MHCII-associated CD4⁺T cell response against gliomas