TREM2: Keeping Pace With Immune Checkpoint Inhibitors in Cancer Immunotherapy

Qiu, Hui; Shao, Zhaogang; Wen, Xin; Jiang, Jeng Kai; Ma, Qinggong; Wang, Yan; Huang, Long Shuang; Ding, Xin; Zhang, Longzhen

doi:10.3389/fimmu.2021.716710

Cited by 14 publications

(13 citation statements)

References 93 publications

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“…However, it is possible that SULF A could elicit inhibitory or stimulatory immune responses in a context-dependent manner. This hypothesis may explain the effective activation of antigen-induced immune protection that SULF A has shown in vivo ( 11 ) and agrees with recent findings on the different modulation of immune cells by TREM2 and PRRs in relation to different microenvironments and physiopathological disorders ( 39 ) ( 40 ).…”

Section: Discussionsupporting

confidence: 90%

The immunoregulatory effect of the TREM2-agonist Sulfavant A in human allogeneic mixed lymphocyte reaction

Barra

Gallo²,

Carbone³

et al. 2023

Front. Immunol.

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IntroductionSulfavant A (SULF A) is a synthetic derivative of naturally occurring sulfolipids. The molecule triggers TREM2-related maturation of dendritic cells (DCs) and has shown promising adjuvant activity in a cancer vaccine model.Methodsthe immunomodulatory activity of SULF A is tested in an allogeneic mixed lymphocyte reaction (MLR) assay based on monocyte-derived dendritic cells and naïve T lymphocytes from human donors. Flow cytometry multiparametric analyses and ELISA assays were performed to characterize the immune populations, T cell proliferation, and to quantify key cytokines.ResultsSupplementation of 10 µg/mL SULF A to the co-cultures induced DCs to expose the costimulatory molecules ICOSL and OX40L and to reduce release of the pro-inflammatory cytokine IL-12. After 7 days of SULF A treatment, T lymphocytes proliferated more and showed increased IL-4 synthesis along with downregulation of Th1 signals such as IFNγ, T-bet and CXCR3. Consistent with these findings, naïve T cells polarized toward a regulatory phenotype with up-regulation of FOXP3 expression and IL-10 synthesis. Flow cytometry analysis also supported the priming of a CD127-/CD4+/CD25+ subpopulation positive for ICOS, the inhibitory molecule CTLA-4, and the activation marker CD69.DiscussionThese results prove that SULF A can modulate DC-T cell synapse and stimulate lymphocyte proliferation and activation. In the hyperresponsive and uncontrolled context of the allogeneic MLR, the effect is associated to differentiation of regulatory T cell subsets and dampening of inflammatory signals.

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Section: Discussionsupporting

confidence: 90%

The immunoregulatory effect of the TREM2-agonist Sulfavant A in human allogeneic mixed lymphocyte reaction

Barra

Gallo²,

Carbone³

et al. 2023

Front. Immunol.

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“…Cells assigned to Cluster 4 were annotated as mesenchymal stromal cells based on their expression of Tagln and S100a6 ( Figure 3 ; Supplementary Table S2 ) ( Marin-Llera and Chimal-Monroy, 2018 ; Luo et al, 2020 ). An immune cell cluster, Cluster 14, was also identified in the Day 2 cultures based on the expression of Tyrobp , Fcer1g , C1qa , C1qb , C1qc , and Trem2 ( Figure 3 ; Supplementary Table S2 ) ( Chen et al, 2021 ; Liang et al, 2021 ; Qiu et al, 2021 ; Dong et al, 2022 ). Cells assigned to Cluster 15 were annotated as erythrocytes based on their expression of Hbby-y and Hba-x ( Figure 3 ; Supplementary Table S2 ) ( Holdener-Kenny and Weaver, 1986 ; Alhashem et al, 2011 ; Chatterjee et al, 2016 ).…”

Section: Resultsmentioning

confidence: 99%

Digits in a dish: An in vitro system to assess the molecular genetics of hand/foot development at single-cell resolution

Fuiten

Yoshimoto

Shukunami

et al. 2023

Front. Cell Dev. Biol.

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In vitro models allow for the study of developmental processes outside of the embryo. To gain access to the cells mediating digit and joint development, we identified a unique property of undifferentiated mesenchyme isolated from the distal early autopod to autonomously re-assemble forming multiple autopod structures including: digits, interdigital tissues, joints, muscles and tendons. Single-cell transcriptomic analysis of these developing structures revealed distinct cell clusters that express canonical markers of distal limb development including: Col2a1, Col10a1, and Sp7 (phalanx formation), Thbs2 and Col1a1 (perichondrium), Gdf5, Wnt5a, and Jun (joint interzone), Aldh1a2 and Msx1 (interdigital tissues), Myod1 (muscle progenitors), Prg4 (articular perichondrium/articular cartilage), and Scx and Tnmd (tenocytes/tendons). Analysis of the gene expression patterns for these signature genes indicates that developmental timing and tissue-specific localization were also recapitulated in a manner similar to the initiation and maturation of the developing murine autopod. Finally, the in vitro digit system also recapitulates congenital malformations associated with genetic mutations as in vitro cultures of Hoxa13 mutant mesenchyme produced defects present in Hoxa13 mutant autopods including digit fusions, reduced phalangeal segment numbers, and poor mesenchymal condensation. These findings demonstrate the robustness of the in vitro digit system to recapitulate digit and joint development. As an in vitro model of murine digit and joint development, this innovative system will provide access to the developing limb tissues facilitating studies to discern how digit and articular joint formation is initiated and how undifferentiated mesenchyme is patterned to establish individual digit morphologies. The in vitro digit system also provides a platform to rapidly evaluate treatments aimed at stimulating the repair or regeneration of mammalian digits impacted by congenital malformation, injury, or disease.

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“…Next, given the enrichment of genes differentially methylated belonging to the Reactome pathway “inflammation”, we measured the gene expression of Triggering Receptor Expressed on Myeloid cells-2 ( TREM2 ), a microglia surface receptor involved in neuroinflammation that is overexpressed in the glioma and associated with tumor progression [ 54 , 55 ]. A pronounced increase of TREM2 was detected in both GBM subgroups compared to the control tissues ( Figure 6 A).…”

Section: Resultsmentioning

confidence: 99%

The Chromatin-Oxygen Sensor Gene KDM5C Associates with Novel Hypoxia-Related Signatures in Glioblastoma Multiforme

Drongitis

Verrillo

Marinis³

et al. 2022

IJMS

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Glioblastoma multiforme (GBM) is a fatal brain tumor without effective drug treatment. In this study, we highlight, for the first time, the contribution of chromatin remodeling gene Lysine (K)-specific demethylase 5C (KDM5C) in GBM via an extensive analysis of clinical, expression, and functional data, integrated with publicly available omic datasets. The expression analysis on GBM samples (N = 37) revealed two informative subtypes, namely KDM5CHigh and KDM5CLow, displaying higher/lower KDM5C levels compared to the controls. The former subtype displays a strong downregulation of brain-derived neurotrophic factor (BDNF)—a negative KDM5C target—and a robust overexpression of hypoxia-inducible transcription factor-1A (HIF1A) gene, a KDM5C modulator. Additionally, a significant co-expression among the prognostic markers HIF1A, Survivin, and p75 was observed. These results, corroborated by KDM5C overexpression and hypoxia-related functional assays in T98G cells, suggest a role for the HIF1A-KDM5C axis in the hypoxic response in this tumor. Interestingly, fluorescence-guided surgery on GBM sections further revealed higher KDM5C and HIF1A levels in the tumor rim niche compared to the adjacent tumor margin, indicating a regionally restricted hyperactivity of this regulatory axis. Analyzing the TCGA expression and methylation data, we found methylation changes between the subtypes in the genes, accounting for the hypoxia response, stem cell differentiation, and inflammation. High NANOG and IL6 levels highlight a distinctive stem cell-like and proinflammatory signature in the KDM5CHigh subgroup and GBM niches. Taken together, our results indicate HIF1A-KDM5C as a new, relevant cancer axis in GBM, opening a new, interesting field of investigation based on KDM5C as a potential therapeutic target of the hypoxic microenvironment in GBM.

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TREM2: Keeping Pace With Immune Checkpoint Inhibitors in Cancer Immunotherapy

Cited by 14 publications

References 93 publications

The immunoregulatory effect of the TREM2-agonist Sulfavant A in human allogeneic mixed lymphocyte reaction

The immunoregulatory effect of the TREM2-agonist Sulfavant A in human allogeneic mixed lymphocyte reaction

Digits in a dish: An in vitro system to assess the molecular genetics of hand/foot development at single-cell resolution

The Chromatin-Oxygen Sensor Gene KDM5C Associates with Novel Hypoxia-Related Signatures in Glioblastoma Multiforme

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