Neutrophils: New Critical Regulators of Glioma

Wang, Guanyu; Wang, Jinpeng; Niu, Chaoshi; Zhao, Yan; Wu, Pengfei

doi:10.3389/fimmu.2022.927233

Cited by 16 publications

(10 citation statements)

References 202 publications

(267 reference statements)

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“…Another limitation is the absence of neutrophils, which are an important cellular component of both the GBM immune microenvironment and antiviral activity; most granulocytes are lost during the Ficoll-Paque density gradient separation method. 26 , 27 , 28 Consequently, we are unable to predict how the presence of neutrophils could alter the observed activation patterns.…”

Section: Discussionmentioning

confidence: 95%

An autologous ex vivo model for exploring patient-specific responses to viro-immunotherapy in glioblastoma

Stavrakaki,

van den Bossche,

Vogelezang

et al. 2024

Cell Reports Methods

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Section: Discussionmentioning

confidence: 95%

An autologous ex vivo model for exploring patient-specific responses to viro-immunotherapy in glioblastoma

Stavrakaki,

van den Bossche,

Vogelezang

et al. 2024

Cell Reports Methods

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“…Likewise, the role of neutrophils in tumor progression remains unclear. In several studies their inflammatory activation has been linked to poor GBM patient outcomes (Wang et al, 2022a ), while experiments on murine models of glioma indicated that neutrophils can limit tumor growth in the early stage of the disease (Magod et al, 2021 ). A similar phenomenon was observed in metastasis, where tumor-entrained neutrophils inhibited spreading of cancer cells into other tissues (Granot et al, 2011 ; López-Lago et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

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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“…Also in GBM patients, high level of the cytokine, both on the periphery and in the tumor microenvironment were linked to increased overall survival (48). Likewise, the role of neutrophils in tumor progression remains unclear, as their inflammatory activation has been linked to bad patient outcomes in several studies (49). However, recent study on the murine models of glioma suggests that neutrophils can limit glioma growth in the early stage of the disease (50).…”

Section: Discussionmentioning

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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Neutrophils: New Critical Regulators of Glioma

Cited by 16 publications

References 202 publications

An autologous ex vivo model for exploring patient-specific responses to viro-immunotherapy in glioblastoma

An autologous ex vivo model for exploring patient-specific responses to viro-immunotherapy in glioblastoma

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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