Exploring the Impact of TREM2 in Tumor-Associated Macrophages

Khantakova, Darya; Brioschi, Simone; Molgora, Martina

doi:10.3390/vaccines10060943

Cited by 30 publications

(15 citation statements)

References 80 publications

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“… 24 , 25 Emerging studies indicate that interactions between microglia/macrophages and T cells may play a dominant role in driving T-cell dysfunction and hence the absence of anti-tumour immunity in glioblastoma and other cancers, 17 , 26 , 27 fuelling tumour growth. For example, recent pre-clinical modelling demonstrates that triggering receptor expressed on myeloid cells 2 (TREM2) expression in TAMs in several cancers is associated with T-cell exhaustion and anti-PD1 therapy resistance, 28 , 29 and TREM2 antibody therapy is being investigated in cancers with TAMs expressing this molecule, 30 although TREM2 relevance in human glioblastoma is yet to be established.…”

Section: Introductionmentioning

confidence: 99%

Clinical impact of anti-inflammatory microglia and macrophage phenotypes at glioblastoma margins

Noorani,

Sidlauskas,

Pellow

et al. 2023

Brain Communications

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Glioblastoma is a devastating brain cancer for which effective treatments are required. Tumour-associated microglia and macrophages promote glioblastoma growth in an immune-suppressed microenvironment. Most recurrences occur at the invasive margin with surrounding brain, yet the relationships between microglia/macrophage phenotypes, T cells and Programmed death-ligand 1 (PD-L1, an immune checkpoint) across human glioblastoma regions are understudied. We performed quantitative immunohistochemical analysis of 15 markers of microglia/macrophage phenotypes (including anti-inflammatory markers TREM2 and CD163, and the low-affinity activating receptor CD32a), T cells, natural killer cells and PD-L1, in 59 human IDH1-wild-type glioblastoma multi-regional samples (n = 177; 1 sample at tumour core, 2 samples at the margins: the infiltrating zone and leading edge). Assessment was made for the prognostic value of markers; the results were validated in an independent cohort. Microglia/macrophage motility and activation (Iba1, CD68), PD-L1, and CD4+ T cells were reduced, and homeostatic microglia (P2RY12) were increased in the invasive margins compared to the tumour core. There were significant positive correlations between microglia/macrophage markers CD68 (phagocytic)/TREM2 (anti-inflammatory) and CD8+ T cells in the invasive margins but not in the tumour core (P<0.01). PD-L1 expression was associated with microglia/macrophage markers (including anti-inflammatory) CD68, CD163, CD32a and TREM2, only in the leading edge of glioblastomas (P<0.01). Similarly, there was a positive correlation between PD-L1 expression and CD8+ T cell infiltration in the leading edge (P<0.001). There was no relationship between CD64 (a receptor for autoreactive T cell responses) and CD8+/CD4+ T cells, or between the microglia/macrophage antigen presentation marker HLA-DR and microglial motility (Iba1) in the tumour margins. Natural killer cell infiltration (CD335+) correlated with CD8+ T cells, and with CD68/CD163/TREM2 anti-inflammatory microglia/macrophages at the leading edge. In an independent large glioblastoma cohort with transcriptomic data, positive correlations between anti-inflammatory microglia/macrophage markers (TREM2, CD163 and CD32a) and CD4+/CD8+/PD-L1 RNA expression were validated (P < 0.001). Finally, multivariate analysis showed high TREM2, PD-L1 and CD32a expression at the leading edge were significantly associated with poorer overall patient survival (hazard ratio = 2.05, 3.42 and 2.11 respectively), independent of clinical variables. In conclusion, anti-inflammatory microglia/macrophages, CD8+ T cells and PD-L1 are correlated in the invasive margins of glioblastoma, consistent with immune-suppressive interactions. High TREM2, PD-L1 and CD32a expression at the human glioblastoma leading edge are predictors of poorer overall survival. Given substantial interest in targeting microglia/macrophages together with immune checkpoint inhibitors in cancer, these data have major clinical implications.

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Section: Introductionmentioning

confidence: 99%

Clinical impact of anti-inflammatory microglia and macrophage phenotypes at glioblastoma margins

Noorani,

Sidlauskas,

Pellow

et al. 2023

Brain Communications

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“…Among “high- SORL1 ” clusters, cluster 7 was characterized by the expression of immediate early genes, SPP1 , a gene associated with tumor-promoting GAMs (Szulzewsky et al, 2015 ), and ID2 involved in pro-tumorigenic polarization of myeloid cells (Huang et al, 2017 ). Cluster 22 showed high expression levels of several microglia/macrophages genes including TREM2 , which was linked before to the pro-tumorigenic properties of tumor-associated macrophages in various cancers (Khantakova et al, 2022 ). At the same time, among “low- SORL1 ” clusters, cluster 9 was characterized by expression of TLR genes as well as pro-inflammatory cytokines IL1A and TNF .…”

Section: Resultsmentioning

confidence: 97%

SorLA restricts TNFα release from microglia to shape a glioma-supportive brain microenvironment

Kaminska,

Ovesen,

Jakiel

et al. 2024

EMBO Rep

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SorLA, encoded by the gene SORL1, is an intracellular sorting receptor of the VPS10P domain receptor gene family. Although SorLA is best recognized for its ability to shuttle target proteins between intracellular compartments in neurons, recent data suggest that also its microglial expression can be of high relevance for the pathogenesis of brain diseases, including glioblastoma (GBM). Here, we interrogated the impact of SorLA on the functional properties of glioma-associated microglia and macrophages (GAMs). In the GBM microenvironment, GAMs are re-programmed and lose the ability to elicit anti-tumor responses. Instead, they acquire a glioma-supporting phenotype, which is a key mechanism promoting glioma progression. Our re-analysis of published scRNA-seq data from GBM patients revealed that functional phenotypes of GAMs are linked to the level of SORL1 expression, which was further confirmed using in vitro models. Moreover, we demonstrate that SorLA restrains secretion of TNFα from microglia to restrict the inflammatory potential of these cells. Finally, we show that loss of SorLA exacerbates the pro-inflammatory response of microglia in the murine model of glioma and suppresses tumor growth.

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“…1C, Dataset S2). Among 'high-SorLA' clusters, cluster 7 was characterized by the expression of immediate early genes and SPP1, a gene associated with tumorpromoting GAMs (15), while cluster 22 showed high expression levels of several microglia/macrophages genes including TREM2, which was linked before to the pro-tumorigenic properties of tumor-associated macrophages in various cancers (16). At the same time, among 'low-SorLA' clusters, cluster 9 was characterized by expression of TLR genes as well as pro-inflammatory cytokines IL1A and TNF.…”

Section: Resultsmentioning

confidence: 99%

SorLA restricts TNFα release from microglia to shape glioma-supportive brain microenvironment

Kamińska

Ovesen

Jakiel

et al. 2023

Preprint

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SorLA, encoded by the gene SORL1, is an intracellular sorting receptor of the VPS10P domain receptor gene family. Although SorLA is best recognized for its ability to shuttle target proteins between intracellular compartments in neurons, recent data suggest that also its microglial expression can be of high relevance for the pathogenesis of brain diseases, including glioblastoma (GBM). Here we interrogated the impact of SorLA on the functional properties of glioma-associated microglia and macrophages (GAMs). In the GBM microenvironment, GAMs are re-programmed and in turn lose the ability to elicit anti-tumor responses. Instead, they acquire glioma-supporting phenotype, which is a key mechanism promoting glioma progression. Our analysis of scRNA-seq data from GBM patients revealed that the pro-tumorigenic and pro-inflammatory properties of GAMs are linked to high and low SORL1 expression, respectively. Using cell models, we confirm that SorLA levels are differentially regulated by the presence of glioma cells and by inflammatory cues. We further show that SorLA acts as a sorting receptor for the pro-inflammatory cytokine TNFalpha to restrain its secretion from microglia. As a consequence, loss of SorLA enhanced the pro-inflammatory potential of microglia, having a remarkable impact on glioma progression. In a murine model of glioma, SorLA-deficient mice develop smaller tumors and show hallmarks of anti-tumor response including altered microglia morphology, enhanced necroptosis, and massive neutrophil influx into the tumor parenchyma. Our findings indicate that SorLA is a key player in shaping the phenotype of GAMs, and its depletion can unlock an anti-tumor response.

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Exploring the Impact of TREM2 in Tumor-Associated Macrophages

Cited by 30 publications

References 80 publications

Clinical impact of anti-inflammatory microglia and macrophage phenotypes at glioblastoma margins

Clinical impact of anti-inflammatory microglia and macrophage phenotypes at glioblastoma margins

SorLA restricts TNFα release from microglia to shape a glioma-supportive brain microenvironment

SorLA restricts TNFα release from microglia to shape glioma-supportive brain microenvironment

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