Lack of TREM2 during anti-PD-1 therapy reprograms intestinal macrophages and microbiota to enhance tumor rejection
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PROVIDER: PRJNA1093426 | ENA |
REPOSITORIES: ENA
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Project description:The gut microbiota and tumor-associated macrophages (TAM) impact anti-PD-1 checkpoint blockade. Reprogramming TAM by either blocking or deleting the macrophage receptor TREM2 attenuates tumor growth, and lack of functional TREM2 enhances tumor elimination by anti-PD-1. Here, we found that anti-PD-1 combined with TREM2 deficiency induces proinflammatory programs in intestinal macrophages and a concomitant expansion of Ruminococcus gnavus (R. gnavus) in the gut microbiota. Gavage of wild-type mice with R. gnavus recapitulated enhancement of anti-PD-1-mediated tumor elimination occurring in the absence of TREM2. The intestinal proinflammatory environment coincided with expansion, increased circulation and migration of TNF-producing CD4+ T cells to the tumor bed. Thus, TREM2 remotely controls anti-PD-1 checkpoint blockade through modulation of the intestinal immune environment and microbiota, with R. gnavus emerging as a potential probiotic agent for increasing responsiveness to anti-PD-1.
2024-05-17 | GSE262811 | GEO
Project description:We aim to investigate the interaction between two of the major genetic risk factors for AD: inheritance of APOEε4 and deficiency of Triggering Receptor Expressed on Myeloid cells 2 (TREM2). Trem2 deletion worsened memory in AD model mice but not in their WT littermates. Interestingly, the lack Trem2 resulted in a significantly less microglia around amyloid plaques in APP mice expressing both APOE isoforms but had no impact on amyloid load. Gene expression analysis identified as Trem2 signature a cluster of highly connected immune response genes, commonly downregulated as a result of Trem2 deletion in all experimental groups, such as Clec7a, Itgax, Cts7, Mpeg1, Csf1r, Cx3cr1, Pik3cg and Spi1/PU.1. In vitro experiments with primary microglia demonstrated a decrease of Aβ phagocytosis in APOE4 versus APOE3 microglia a difference that was augmented by the absence of Trem2. Our data demonstrate that the lack of Trem2 differentially impact the phenotype and brain transcriptome of APP mice expressing human APOE isoforms probably reflecting the difference between APOE isoforms to transport lipids that can affect APOE receptor-binding properties.
2020-07-09 | GSE144125 | GEO
Project description:Trem2 Agonist Reprograms Foamy Macrophages to Promote Atherosclerotic Plaque Stability
| PRJNA1078390 | ENA
Project description:The prevailing view is that myeloid cells in the tumor microenvironment (TME) are immunosuppressive and promote glioblastoma (GBM) progression. However, myeloid cells have the functional plasticity to restrict or support tumor cell growth. TREM2 plays important roles in brain microglial function in neurodegenerative diseases, but the role of TREM2 in the GBM TME has not been examined. We found TREM2 is highly expressed in myeloid subsets, including macrophages and microglia in human and mouse GBM tumors and that high TREM2 expression correlates with poor prognosis in GBM patients. TREM2 loss of function in human macrophages and mouse myeloid cells increased tumoricidal capacity. TREM2 in myeloid cells restricts IFNγ-induced immunoactivation and proinflammatory polarization. In orthotopic mouse GBM models, Trem2-/- mice and mice with acute brain Trem2 reduction demonstrate survival benefit. Trem2 inhibition reprograms myeloid phenotypes and increases PD-1+CD8+ T cells in the TME. Trem2 deficiency enhances the effectiveness of anti-PD-1 treatment and may represent a therapeutic strategy for GBM patients.
2023-05-12 | GSE226292 | GEO
Project description:The prevailing view is that myeloid cells in the tumor microenvironment (TME) are immunosuppressive and promote glioblastoma (GBM) progression. However, myeloid cells have the functional plasticity to restrict or support tumor cell growth. TREM2 plays important roles in brain microglial function in neurodegenerative diseases, but the role of TREM2 in the GBM TME has not been examined. We found TREM2 is highly expressed in myeloid subsets, including macrophages and microglia in human and mouse GBM tumors and that high TREM2 expression correlates with poor prognosis in GBM patients. TREM2 loss of function in human macrophages and mouse myeloid cells increased tumoricidal capacity. TREM2 in myeloid cells restricts IFNγ-induced immunoactivation and proinflammatory polarization. In orthotopic mouse GBM models, Trem2-/- mice and mice with acute brain Trem2 reduction demonstrate survival benefit. Trem2 inhibition reprograms myeloid phenotypes and increases PD-1+CD8+ T cells in the TME. Trem2 deficiency enhances the effectiveness of anti-PD-1 treatment and may represent a therapeutic strategy for GBM patients.
2023-05-12 | GSE226172 | GEO
Project description:To elucidate the impact of Trem2 agonist on aortic gene expression during atherosclerosis.
2024-04-18 | GSE256189 | GEO
Project description:Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2(-/-)) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2(-/-) microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2(-/-) microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage. Two STAGE (6weeks 12 weeks),
2015-07-06 | E-GEOD-70475 | biostudies-arrayexpress
Project description:Targeting EZH2 reprograms intratumoral regulatory T cells to enhance cancer immunity
| PRJNA470833 | ENA
Project description:Triggering receptor expressed on myeloid cells 2 (Trem2) is a myeloid cell-specific gene expressed in microglia, whose variants are associated with multiple neurodegenerative diseases. TREM2 receptor modulates phagocytosis, cytokine production and metabolism, enabling appropriate surveillance of the brain by microglia and ensuring their proper response to damage signals. Here, we demonstrate that TREM2 plays a key role in controlling the bioenergetic profile of pyramidal neurons during development. In the absence of Trem2, developing neurons in hippocampal CA1 -but not in CA3- subfield display compromised energetic metabolism and defective basal, maximal and ATP-dependent respiration, accompanied by reduced mitochondrial mass and abnormal organelle ultrastructure. This is paralleled by a significant transcriptional rearrangement of hippocampal pyramidal neurons at birth, with a pervasive alteration of metabolic, oxidative phosphorylation and mitochondrial signatures. The developmental trajectories of the excitatory lineages indicate that lack of Trem2 causes a delay in the maturation of CA1 neurons, paired with specific alterations in the mitochondrial TOM complex which persist in the mature hippocampus. In addition, the mitochondrial defects and faulty neuronal differentiation are maintained also after neuron isolation from the brain context, suggesting that the lack of TREM2-mediated communication between microglia and neurons at early developmental windows is sufficient to derange the forthcoming maturation of neuronal metabolism. Our results unveil a novel role of TREM2 in controlling neuronal development by regulating the metabolic fitness of neurons in a region-specific manner.
2024-01-15 | GSE249036 | GEO