The therapeutic potential of TREM2 in cancer

Wolf, Elysa M.; Fingleton, Barbara; Hasty, Alyssa H.

doi:10.3389/fonc.2022.984193

Cited by 21 publications

(15 citation statements)

References 45 publications

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“…This data indicates Trem2 promotes phagocytosis in the mouse brain TIME, and it is particularly important on DCs, suggesting a tractable potential target for enhancing phagocytosis and antigen presentation in gliomas Collectively, our human and mouse data position TREM2 as important regulator of phagocytosis in glioma. Emerging studies show both cell intrinsic as well immunomodulatory roles of TREM2 in cancer (Wolf et al, 2022). TREM2 is expressed in cancer cells and can function as either an oncogene or tumor suppressor (Deczkowska et al, 2020), but most studies revolve around immunosuppressive functions of TREM2 given its high expression in tumor associated MACs (Katzenelenbogen et al, 2020) ( Molgora et al, 2020).…”

Section: Trem2 + Mg and DC Mediate Phagocytosis Of Gliomasmentioning

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: Trem2 + Mg and DC Mediate Phagocytosis Of Gliomasmentioning

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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“…Exactly like in the in vitro experiments, the absence of toxicity and lethality and the overtime fluorescence stability in the zebrafish model demonstrated the reliability of this molecule for application to more complex living systems. Further considering the therapeutic potential of targeting TREM2 in the tumor microenvironment, the biovisualization and permanence of 4 in digestive organs was particularly attractive in light of the similarity of the zebrafish and human cancer biology of gastrointestinal disorders and of the resulting development of the zebrafish model for the study of various diseases such as digestive system tumors. , These evidence make finally possible to approach in vivo anticancer experiments in more complex tumor models for the evaluation of Sulfavants' effects.…”

Section: Resultsmentioning

confidence: 99%

BODIPY-Based Analogue of the TREM2-Binding Molecular Adjuvant Sulfavant A, a Chemical Tool for Imaging and Tracking Biological Systems

Fioretto,

Gallo,

Mercogliano

et al. 2024

Anal. Chem.

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Recently, we described synthetic sulfolipids named Sulfavants as a novel class of molecular adjuvants based on the sulfoquinovosyl-diacylglycerol skeleton. The members of this family, Sulfavant A (1), Sulfavant R (2), and Sulfavant S (3), showed important effects on triggering receptor expressed on myeloid cells 2 (TREM2)-induced differentiation and maturation of human dendritic cells (hDC), through a novel cell mechanism underlying the regulation of the immune response. As these molecules are involved in biological TREM2-mediated processes crucial for cell survival, here, we report the synthesis and application of a fluorescent analogue of Sulfavant A bearing the 4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene moiety (Me 4 -BODIPY). The fluorescent derivative, named PB-SULF A (4), preserving the biological activity of Sulfavants, opens the way to chemical biology and cell biology experiments to better understand the interactions with cellular and in vivo organ targets and to improve our comprehension of complex molecular mechanisms underlying the not fully understood ligand-induced TREM2 activity.

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“…TREM2 -expressing macrophages have been associated with a poor prognosis in cancer patients (36) . Even though this scenario was observed for RTM_LA and Mac_IFN in LIHC (Fig.…”

Section: Resultsmentioning

confidence: 99%

Identification of novel myeloid-derived cell states with implication in cancer outcome

Maklouf

Guimarães

Teixeira

et al. 2023

Preprint

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Immunotherapies provide long-lasting responses across a wide range of cancers; however, only a fraction of patients responds to them. Multiple reasons contribute to the failure, including the existence of myeloid-derived cells (MDCs) within tumors. Due to their high plasticity, these cells display numerous cell states and, as a result, distinct pro-tumorigenic behaviors, making them interesting targets. However, the creation of cutting-edge anticancer therapies is hampered by the lack of MDC-specific markers. To fully define the MDC landscape in solid tumors, we combined single-cell RNA-Seq from 13 public datasets, including samples from seven different cancers and normal samples, yielding the largest collection of MDC subpopulations within the tumor microenvironment. We identified five major lineages subdivided into one mast cell cluster, three neutrophils, eight dendritic cells, six monocytes, and eleven macrophage states. Transcriptional profiles coupled with deconvolution estimates of cell populations in large cohorts revealed five MDC subpopulations as independent prognostic markers in different cancer types, including resident tissue interstitial macrophages and FCGR3A+ monocytes associated with an unfavorable clinical outcome in ovarian and breast cancer patients, respectively. Our work reveals that TREM2+ macrophages can be distinguished in different populations and associated with distinct prognoses. By analyzing a Brazilian cohort of ovarian cancer, we found that TREM2+ macrophages are associated with a better prognosis, indicating that their role might be dependent on the tumor niche and co-expression of immunosuppressive markers. Collectively, this atlas reveals in high-resolution the heterogeneous MDC identity as well as new avenues for understanding and manipulating their fate in cancer.

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The therapeutic potential of TREM2 in cancer

Cited by 21 publications

References 45 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

BODIPY-Based Analogue of the TREM2-Binding Molecular Adjuvant Sulfavant A, a Chemical Tool for Imaging and Tracking Biological Systems

Identification of novel myeloid-derived cell states with implication in cancer outcome

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