Skip to content
naulon
Get started

No retraction, correction or concern found when last checked on Oct 25, 2026.

Tumor-Associated Microglia and Macrophages in the Glioblastoma Microenvironment and Their Implications for Therapy

Rikke Sick Andersen, Atul Anand, Dylan Scott Lykke Harwood and 1 more

Cancers · 2021 · Review · CC BY

doi:10.3390/cancers13174255

Abstract

Simple Summary. Patients with glioblastoma—the most frequent and malignant primary brain tumor—have a poor prognosis with a median survival of less than 15 months. Despite extensive research, treatment of glioblastoma has not improved since 2005. Most therapeutic strategies have focused on eliminating the glioblastoma cells themselves, but tumor-infiltrating immune cells are potential targets as well. Glioblastomas are highly infiltrated with tumor-associated microglia and macrophages (TAMs), which are known to support the glioblastoma cells and promote tumor progression. Although broad categories are used to describe TAM phenotypes, recent technological advances have allowed deeper insights into their phenotypical differences. A better understanding of how known and unknown TAM phenotypes interact with their neighboring cancer cells may be crucial for establishing effective treatment strategies for glioblastoma patients. In this review, we give an updated overview of the role of TAMs in glioblastoma, and we discuss TAM–glioblastoma crosstalk and review potential therapeutic TAM-targeting strategies.

Abstract. Glioblastoma is the most frequent and malignant primary brain tumor. Standard of care includes surgery followed by radiation and temozolomide chemotherapy. Despite treatment, patients have a poor prognosis with a median survival of less than 15 months. The poor prognosis is associated with an increased abundance of tumor-associated microglia and macrophages (TAMs), which are known to play a role in creating a pro-tumorigenic environment and aiding tumor progression. Most treatment strategies are directed against glioblastoma cells; however, accumulating evidence suggests targeting of TAMs as a promising therapeutic strategy. While TAMs are typically dichotomously classified as M1 and M2 phenotypes, recent studies utilizing single cell technologies have identified expression pattern differences, which is beginning to give a deeper understanding of the heterogeneous subpopulations of TAMs in glioblastomas. In this review, we evaluate the role of TAMs in the glioblastoma microenvironment and discuss how their interactions with cancer cells have an extensive impact on glioblastoma progression and treatment resistance. Finally, we summarize the effects and challenges of therapeutic strategies, which specifically aim to target TAMs.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 25, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

Glioblastoma is ranked as a grade 4 glioma by the World Health Organization (WHO) and is the most frequent and malignant adult brain tumor. The median survival is less than 15 months, and 95% of patients die within 5 years of diagnosis, because an effective treatment has not yet been found. Currently, the standard treatment for glioblastoma is surgery followed by radiation therapy along with temozolomide chemotherapy.

The glioblastoma microenvironment consists of several types of cells that affect the cancer cells in various ways. The tumor microenvironment (TME) primarily contains tumor-associated microglia and macrophages (TAMs), which constitute up to 30% of the total tumor. TAMs secrete various factors—e.g., cytokines and growth factors—which lead to or support different biological functions in the TME, such as stemness, proliferation, angiogenesis, cancer cell migration, and immune suppression. Notably, specific subsets of TAMs are associated with poor survival in glioma patients. Over the past years, TAMs have become an attractive target to treat glioblastoma patients, and many studies and clinical trials have focused on this.

In this article, we review and discuss the existence of TAM subtypes in the glioblastoma microenvironment based on recent cutting-edge research as well as well-established knowledge. We discuss TAM–tumor crosstalk and the extensive impact TAMs have on glioblastoma progression. Finally, we consider promising therapeutic concepts targeting TAMs.

2. TAMs in the Glioblastoma Microenvironment

The TME in glioblastoma consists of many different cell types. Various immune cells reside in the TME and affect the cancer cells. Myeloid cells are the most frequent cells including myeloid-derived suppressor cells (MDSCs), dendritic cells, neutrophils, in addition to TAMs, which are the most abundant in the TME. The main lymphoid cells present in glioblastoma are T cells; however, they are infrequent and comprise less than 2% of the tumor with CD8+ cytotoxic T cells being more frequent than CD4+ helper T (Th) cells and regulatory T cells (Tregs). The role of cytotoxic T cells is to eradicate abnormal cells, such as cancer cells, however, when present, cytotoxic T cells are often highly exhausted and dysfunctional, explaining why they are not as effective in glioblastoma as they are in other cancers. Th cells assist in activating the cytotoxic T cells, whereas Tregs are immune inhibitory cells, which inhibit the cytotoxic T cell response. In addition, non-immune cells like astrocytes, neurons, endothelial cells, and pericytes are present in the TME and support the tumor in different ways.

As mentioned, TAMs comprise up to 30% of the entire tumor and their presence has been associated with increased tumor growth, increased invasiveness, and inferior survival. TAMs are, in contrast to cancer cells, genetically stable, making these cells favorable therapeutic targets. TAMs are, however, not a uniform group of cells. They comprise both microglia and macrophages. The tumor-infiltrating macrophages can be blood-derived or microglia-derived. Previously, microglia and macrophages were distinguished by their differential expression of CD45; however, CD45 has been shown to occasionally be upregulated in microglia to the same level as in macrophages. Today, a few markers have been identified for human microglia (Tmem119 P2RY12), but no well-defined markers for human macrophages have been identified. CD49d has been suggested to distinguish macrophages, although this requires further validation. Microglia and macrophages may morphologically present as two distinct populations, but in some cases, the co-expression of microglia markers and markers frequently expressed by macrophages have been observed.

Historically, two main TAM phenotypes have been described: the classical, pro-inflammatory M1 TAMs and the alternatively activated, anti-inflammatory M2 TAMs. M2 macrophages have been divided into three subtypes—M2a, M2b, and M2c—with very different functions, such as the involvement in allergy, immune regulation, and tissue remodeling. Simplistically, M1 TAMs are anti-tumorigenic, secreting pro-inflammatory cytokines, like tumor necrosis factor-α (TNF-α), and mediating Th1 responses. M2 TAMs have pro-tumorigenic functions and secrete anti-inflammatory cytokines—such as transforming growth factor-β (TGF-β)—which inhibit cytotoxic T cells and attract Tregs and MDSCs. Furthermore, they produce factors supporting extracellular matrix remodeling as well as angiogenesis. However, these two main TAM phenotypes have been revealed to be the ends of a spectrum, and TAMs are now considered as cells with high plasticity, which can assume many functions and phenotypes. In addition, heterogeneous populations of TAMs co-expressing M1 and M2 markers have been identified in both glioblastoma as well as a model of CNS injury, which illustrates the presence of differential phenotypes, as well as phenotype switching (Figure 1). Moreover, an unforeseen myeloid cell heterogeneity was observed in an orthotopic glioma mouse model, underlining the substantial heterogeneity of these cells.

A proper characterization of the functional and phenotypical heterogeneity of TAMs requires future studies to investigate the spatial context of these cells, and how they interact with neighboring cells. These studies are beginning to emerge, with the very recent identification of a subpopulation of HMOX1-expressing TAMs that drive T cell exhaustion. This study showed a correlation between T cell exhaustion and HMOX1-expressing myeloid cells in a spatial context. Another recent study identifies six different subsets of TAMs with distinct gene signatures that associate with, e.g., hypoxia, phagocytosis or an interferon-induced signature. In addition, this study associates TAMs with T cell suppression and angiogenesis.

Most studies describe TAMs in the tumor core. However, there is high histological heterogeneity in glioblastomas, with the presence of different histological structures, such as tumor core, pseudopalisading cells around necrosis, microvascular proliferation and tumor periphery. TAM presence varies between the different structures, with the highest frequency in the tumor core and around necrotic areas with hypoxia (Figure 1). It has been shown that TAMs in the tumor core are mainly macrophages with an anti-inflammatory, M2-like profile, while TAMs in the periphery are mainly microglia with a more pro-inflammatory, M1-like profile.

Studies associate different TAM populations with poor prognosis. Several studies have associated infiltration of both M2-like microglia and macrophages with inferior survival as well as resistance to radiotherapy in high-grade gliomas. One of the studies showed that the presence of M2-like, CD204+ TAMs is an independent predictor of survival in glioblastomas. In other studies, only macrophages display the anti-inflammatory and pro-angiogenic phenotype, while microglia are classified as pro-inflammatory. These studies suggest that only macrophages and not microglia are pro-tumorigenic. In addition, it has been proposed that the presence of macrophages in low-grade gliomas correlates with inferior survival, and they are more abundant in higher-grade gliomas than microglia. The therapeutic targeting of pro-tumorigenic TAMs is highly favorable and is of great focus in the search to improve the survival of glioblastoma patients.

The glioblastoma TME is complex, with tumor heterogeneity being a large contribution to complexity. Different molecular subtypes exist: proneural, mesenchymal, and classical, and these are associated with copy number amplification in PDGFRA, inactivating mutations in NF1, and copy number amplification in EGFR, respectively. These subtypes can either be the main characteristic of an individual tumor—e.g., a mainly mesenchymal tumor—or the different subtypes can be present in different regions within the same tumor. TAMs are most abundant in the mesenchymal subtype, which generally has the highest degree of infiltrating immune cells. NF1 deficiency is a characteristic of malignant cells of the mesenchymal subtype and has also been linked to increased chemoattraction and infiltration of TAMs.

3. Glioblastoma and TAM Crosstalk

Glioblastoma cells secrete several factors that regulate TAM phenotype, survival and recruitment to the TME. After recruitment to the tumor, TAMs support and promote glioblastoma cell migration, invasion, stemness, proliferation, angiogenesis and immune suppression. Below we discuss the latest and most well established knowledge on these aspects, first with a focus on glioblastoma-derived factors and next on TAM-derived factors.

3.1. The Influence of Glioblastoma Cells on TAMs

Several factors are involved in the crosstalk between glioblastoma cells and TAMs (Figure 2). Most of these factors either attract and recruit TAMs to the tumor or polarize the TAMs towards a more pro-tumorigenic M2-like phenotype. Thus, the tumor modifies and exploits the TAMs to support its malignant progression. The majority of these known glioblastoma-secreted factors are cytokines, and many of these function as chemo-attractants, such as C-X3-C motif chemokine (CX3C) ligand 1 (CX3CL1), C-C motif chemokine ligand (CCL) 2 (CCL2), macrophage inhibitory cytokine-1 (MIC-1), and colony-stimulating factor 1 (CSF1). The chemokine CX3CL1 is involved in the recruitment of TAMs to the glioblastoma TME via tumor secretion and subsequent binding to CX3C receptor 1 (CX3CR1) on TAMs.

Moreover, C-X-C motif chemokine ligand (CXCL) 16 (CXCL16) is secreted by glioblastoma cells, and by signaling through C-X-C motif chemokine receptor (CXCR) 6 (CXCR6) it polarizes TAMs towards the M2-like phenotype. CXCL16/CXCR6 signaling can also act directly on tumor cells to promote their proliferation, migration and invasion in both human glioblastoma cells in vitro as well as in a glioma mouse model. IL-33 secreted by glioblastoma cells is involved in TAM recruitment and polarization towards pro-tumorigenic M2-like TAMs. In addition, IL-33 expression is associated with poor survival in glioblastoma patients. The cytokine osteopontin (OPN) is secreted by glioblastoma cells, and it may affect these in a variety of ways, such as induction of invasion, survival and angiogenesis, but it also recruits macrophages to the TME via integrins and maintains the M2-like phenotype. Additionally, glioma-derived CCL2 recruits TAMs to the tumor, but at the same time takes part in a feed-forward mechanism, where it induces IL-6 production in microglia, which consecutively affects glioma cells by increasing their invasiveness. TGF-β is a multifunctional cytokine, which is secreted by both TAMs and glioblastoma cells, and it promotes various processes in the tumor, like cancer cell proliferation, invasion, stemness, angiogenesis and immune suppression, but TGF-β also recruits TAMs to the TME and plays a role in M2-like polarization.

In addition to cytokines, glioma cells also produce the growth factor glial cell–derived neurotrophic factor (GDNF), which plays a critical role in controlling TAM recruitment to the TME through GDNF family receptor alpha 1 and 2 expressed by TAMs. Interestingly, depleting GDNF in a glioma cell line and implanting the cells in mouse brains shows reduced tumor size and prolonged survival of the mice.

Glioblastoma cells also produce additional factors. For instance, the cell cycle regulator cellular communication network factor 1 (CCN1) plays an important role in cancer progression and inflammatory response in different solid cancers. In glioblastoma, secretion of CCN1 is reported to result in macrophage infiltration in an in vivo model through the upregulation of integrins. Another glioblastoma-derived factor influencing TAMs is periostin, which is secreted to recruit TAMs to the tumor. Periostin expression correlates with TAM density, and depletion of periostin in glioblastoma cells reduces TAM recruitment and inhibits tumor growth in mice bearing glioma stem-like cell-derived xenografts via integrin αvβ3 signaling. Furthermore, PTEN deficient glioma cells have been shown to secrete lysyl oxidase (LOX), which recruits macrophages to the tumor. In a PTEN-null glioblastoma xenograft mouse model, LOX inhibition decreases macrophage infiltration and tumor growth. LOX-mediated macrophage recruitment triggers the secretion of OPN by macrophages, which further recruits additional macrophages. Recently, Wnt-induced signaling protein 1 (WISP1) was reported to be secreted by glioblastoma stem-like cells and to promote the survival of both glioblastoma cells and TAMs by Akt signaling. Targeting WISP1 signaling decreases the tumor and TAM load in glioblastoma mouse models.

Finally, extracellular vesicles released by glioblastoma cells play a critical role in tumor progression. Glioblastoma cells release extracellular vesicles containing programmed death (PD) ligand 1 (PD-L1) and phospho-STAT3, which can be taken up by TAMs and polarize them towards the M2-like phenotype. Additionally, extracellular vesicles from glioblastoma cells are also known to influence primary human microglia by increasing their expression of matrix metalloproteinase 14 (MMP14), vascular endothelial growth factor (VEGF), and IL-6, thereby making them more pro-tumorigenic. Similarly, glioma-derived exosomes can carry microRNAs (miRNAs) that after uptake by TAMs can affect TAM phenotype and functions. Of these, miR-1246 has been shown to induce M2 polarization, which involves the inhibition of the NF-κB pathway as well as activation of the STAT3 pathway. The oncogenic miR-21 has been shown to increase microglial proliferation.

Some tumor-derived factors influencing TAMs have been therapeutically targeted in clinical trials. E.g., CCL2 was inhibited to reduce TAM recruitment to the tumor, and CD47 has been targeted to reduce its inhibitory effect on TAM phagocytosis. These will be described further in the following section.

3.2. The Influence of TAMs on Glioblastoma Cells

After their recruitment to the glioblastoma TME, many TAMs differentiate into the M2-like phenotype. High expression of M2-like TAM markers—e.g., CD204 and CD163—in glioblastoma are associated with poor survival and an aggressive glioma subtype. TAMs produce and secrete various factors—including cytokines and growth factors—which control different biological functions in the TME, such as proliferation, stemness, angiogenesis, migration, invasion, and immune suppression. Below, we discuss TAM effects on glioblastoma cells (Figure 3).

Sustained cell proliferation and stem cell-like characteristics are important factors in glioblastoma biology and sustained proliferative signaling is a hallmark of glioblastoma. Glioblastoma stem-like cells are a critical factor in glioblastoma progression and relapse. They have been described to reinitiate tumor growth after the removal of therapeutic pressure, leading to tumor recurrence. Many signaling factors released by TAMs play critical roles in glioblastoma stemness and proliferation. Epidermal growth factor (EGF) receptors (EGFRs) play crucial roles in glioma cell proliferation, and tumor-associated microglia secrete EGF that activates EGFR in glioblastoma cells. In addition, stress-induced phosphoprotein 1 (STIP1) secreted by TAMs induces proliferation of glioma cells in vitro, while IL-10 was shown to promote glioma cell proliferation via JAK2/STAT3 signaling in a glioma model. Recent results show that TAMs secrete IL-1β, which promotes the rate of glycolysis in glioma cells through glycerol-3-phosphate dehydrogenase (GPD) enzyme. Hindering IL-1β signaling in TAMs attenuated the glycolysis rate and cell proliferation of glioma cells in vitro. The same study showed a positive association between the activation of GPD and IL-1β expression, TAM recruitment, tumor grade, and reduced survival in human glioblastoma patients. TGF-β also increases the proliferation of glioblastoma cells. Under normal circumstances, TGF-β has cytostatic effects, but in cancer TGF-β signals via Smad4, which induces expression of platelet derived growth factor B (PDGFB) and thereby glioma proliferation. The multifunctional TGF-β can also enhance stemness in glioma cells. Moreover, a glioblastoma study shows that TAMs overexpress macrophage receptor with collagenous structure (MARCO), which drives a phenotypic shift to the mesenchymal subtype, as well as induce invasiveness, proliferation and therapeutic resistance. CCL8 and hypoxia-induced CCL4 signals also induce an invasive phenotype and glioma stem-like traits in glioblastoma cells. Additionally, TAMs are also known to secrete pleiotrophin (PTN) that promotes glioblastoma tumor growth and stem cell maintenance via protein tyrosine phosphatase receptor type Z1 (PTPRZ1) signaling. Although the above-mentioned factors play crucial roles in stemness and glioma cell proliferation, detailed mechanisms and further knowledge is required from fresh human glioblastoma tissue.

Cancer cells require a continuous supply of oxygen and nutrients, and angiogenesis is part of the biological program to support this. After recruitment to the TME, TAMs release different factors—such as VEGF, IL-6, Angiopoietin 2 (ANG2), and insulin-like growth factor-binding protein 1 (IGFBP1)—to stimulate neovascularization in the tumor. The angiogenic role of VEGF-A to stimulate endothelial ECM degradation, proliferation, and migration to form new blood vessels in tumors is well established, and it is an important mediator of hypoxia-induced tumor growth in glioblastoma. VEGF-A is both tumor- and TAM-derived. It has been shown that transgenic mice with VEGF-A-deficient myeloid cells implanted with glioma cells have delayed tumor growth and prolonged survival, indicating that TAM-derived VEGF-A plays a significant role in tumor progression. However, other factors play essential roles in glioblastoma angiogenesis as well, which is supported by the fact that anti-VEGF-A treatment with Bevacizumab is ineffective. The multifunctional cytokine TGF-β can act as an angiogenic factor by upregulating VEGF as well as the plasminogen activator inhibitor (PAI-I), which is involved in vessel maturation. Recently, high levels of macrophage migration inhibitory factor (MIF) have been associated with tumor recurrence and poor survival, and MIF is now emerging as a promising anti-angiogenic target in glioblastoma. Hypoxia-induced MIF has been shown to be released in the glioblastoma TME promoting vasculogenic structure, and its expression correlates with the expression of VEGF. Furthermore, microglia produce IGFBP1 in response to glioma-derived CSF1, and IGFBP1 has been shown to induce angiogenesis in glioma cells. Versican is a proteoglycan that has various pro-tumorigenic properties. It was revealed to increase the survival and angiogenic properties of glioblastoma cells in vitro and in vivo in mice. Alternative proangiogenic factors were recently suggested to be expressed by TAMs infiltrating glioblastomas having high granulocyte infiltration. These TAMs showed high expression of CD13 and CXCL2, which may promote angiogenesis independent of VEGF.

Extracellular matrix (ECM) in glioblastoma is an important structural factor that contains mainly proteoglycans and glycosaminoglycans. TAM-derived factors—such as CCL8, CCL5, and MMPs—play crucial roles in tumor invasion and progression by participating in ECM degradation. A mouse glioblastoma study showed that CCL8, primarily secreted by TAMs, helps in the formation of pseudopodia-like structures in glioblastoma cells via C-C motif chemokine receptor (CCR) 1 (CCR1) or CCR5 axes, which promotes tumor migration and invasion. Additionally, CCL8 activates the ERK1/2 pathway that also leads to invasion as well as increased stemness of glioblastoma cells. Targeting glioma cells with an ERK1/2 inhibitor leads to decreased invasion. Additionally, microglia-derived CCL5 triggers upregulation of MMP2 in glioma cells through calcium and Akt signaling, which in response promotes ECM degradation and invasiveness in glioma. Similarly, MMP2 can also be expressed by microglia themselves. Moreover, M2-like macrophages express MMP9 and MMP14, which are also associated with ECM degradation and facilitate cancer cell migration through the TME. Microglia also secrete TGF-β, which has been shown to have an invasion-promoting role in glioblastoma cells both in vitro and in vivo in mice. The effect of microglia-derived TGF-β may be mediated by upregulated MMPs and downregulated tissue inhibitor of metalloproteinases (TIMP). As mentioned earlier, glioma cells secrete CCL2, which induces IL-6 secretion in microglia thereby increasing glioma invasiveness. The enhanced invasion may be mediated by an IL-6-induced increase in STAT3 signaling and upregulation of MMP2 in glioma cells.

Apart from promoting cancer cells, TAMs also play crucial roles in T cell inactivation and immune suppression leading to tumor immune evasion. M2-like TAMs express PD-L1 that may lead to T cell inactivation. Treating a glioblastoma mouse model with anti-PD-L1 antibody shows reduced infiltration of M2-like TAMs and reduced tumor growth. Notably, monocytes from glioblastoma patients have elevated levels of PD-L1 compared to healthy individuals, and co-culturing PD-L1+ monocytes with T cells leads to T cell apoptosis. Additionally, a glioblastoma mouse study indicates that anti–PD-L1 treatment may boost a radiotherapy response by mediating activation of T cells and macrophages. The Fas ligand (FasL) is also well known for its role in immune suppression by inducing T cell apoptosis. Evidence from a mouse glioma model suggests that microglia are a major source of FasL in gliomas and inhibiting FasL elevates the leukocyte infiltration in tumors. In addition, TAMs secrete CCL2, which is critical for the recruitment of Tregs and MDSCs to the tumor. High expression of CCL2 in glioblastoma patients is associated with poor survival. Additionally, M2-like TAMs secrete IL-10 and TGF-β that play critical roles in tumor immune evasion by inhibiting Th1 and cytotoxic T cell effector molecules, inhibiting antigen presentation by downregulating MHC class II on glioma cells, and attracting immune-suppressive Tregs and MDSCs.

The RNA regulator human antigen R (HuR) complex post-transcriptionally regulates several mRNAs in the STAT and NF-kB signaling pathways, and it plays a role in shaping the TAM molecular signature and phenotype. The deletion of the HuR gene in TAMs leads to the accumulation of pro-inflammatory M1-like TAMs and cytotoxic T cells in the TME, which further causes tumor suppression and prolonged survival in a HuR knockdown mouse model of glioblastoma.

As illustrated in this section, extensive crosstalk between TAMs and cancer cells occurs in the glioblastoma TME. Many attempts have been made to target TAM–glioblastoma interactions for therapeutic intervention in clinical trials, and these are subject for discussion in the next section.

4. Glioblastoma Treatment—Therapies Targeting TAMs and Challenges

For more than a decade, only limited advancement in the treatment of glioblastoma has been achieved despite extensive efforts to develop new therapeutic strategies. TAM-targeting strategies have been and are being clinically tested. TAMs may be responsible for part of glioblastoma treatment resistance. Radiation therapy leads to TAM recruitment to the tumor. Especially the numbers of macrophages are increased in the tumor, and upon recurrence, there is a higher macrophage-to-microglia ratio. Furthermore, radiotherapy induces a more M2-skewed TME, which might be explained by increased radio-resistance of M2-like TAMs, as suggested by a preclinical glioblastoma study. One study found TAMs to be involved in the radio-resistance of glioblastoma cells by the secretion of TNF-α, which increases nuclear factor-κB (NF-κB) signaling and induces the radio-resilient mesenchymal subtype. The study also found that the mesenchymal gene signature, CD44 expression and NF-κB activation correlated with inferior survival and poor radiation response.

TAMs can be therapeutically targeted in different ways: (1) targeting TAM recruitment to the tumor, (2) reprogramming TAM polarization towards a more anti-tumor, M1-like phenotype, or (3) decreasing or eliminating tumor-promoting M2-like TAMs (Table 1 and Figure 4).

4.1. Targeting TAM Recruitment

TAM recruitment can be prevented by inhibiting the chemokine gradient axes involved in recruiting TAMs to the tumor, such as the CCL2-CCR2 and CXCL12-CXCR4 axes. The inflammatory chemokines CCL2 and CXCL12 attract CCR2- and CXCR4-expressing monocytes, microglia, and macrophages. When secreted by cancer cells, monocytes, microglia and macrophages are recruited to the tumor, contributing to an immunosuppressive TME.

Anti-CCL2 monoclonal antibodies (mAbs) and small molecule inhibitors of CCR2 have been tested in phase I/II clinical trials in solid tumors. These treatments are generally well-tolerated, although only CCR2 inhibition combined with chemotherapy obtained objective responses and awaits further investigation in randomized trials.

A CXCR4 antagonist has been investigated in glioblastoma patients. In combination with Bevacizumab (anti-VEGF), it showed no effect on survival, but in combination with chemoradiation (temozolomide), median overall survival was improved to 21.3 months, compared to 14.6 months for chemoradiation alone. This is being investigated further in a follow-up trial (NCT03746080).

4.2. Reprogramming TAM Polarization and Increasing Anti-Tumor TAMs

Numerous studies aim at increasing the M1/M2 TAM ratio to polarize TAMs towards the pro-inflammatory, anti-tumorigenic M1-like phenotype, and several targets are being investigated—also in the clinic.

CD47 is a checkpoint molecule inhibiting macrophage phagocytosis upon binding to the signal-regulatory protein-α (SIRPα), and high expression correlates with poor survival in glioblastoma. Inhibition of CD47 leads to increased phagocytosis of cancer cells by TAMs in experimental glioblastoma models, as well as an increase in M1-like macrophages and improved survival in glioblastoma animal models. Furthermore, recent preclinical studies have shown that a combination of CD47-SIRPα axis-targeting and autophagy inhibitors may increase the anti-tumor effects of CD47 inhibition, which may in addition increase the effect of anti-PD-1 treatment. Small molecule inhibitors of CD47 and anti-CD47 mAbs are being tested in the clinic in both solid and hematological cancers, and results are pending.

Toll-like receptors (TLRs) are expressed by macrophages and activation with different TLR ligands polarizes TAMs to an M1-like phenotype. TLR agonists have been tested in clinical trials in both solid tumors and lymphomas, although showing little efficacy. The effects in gliomas are currently being investigated in a few clinical trials, however, only as immune adjuvants for immunotherapies (NCT03392545, NCT01204684).

CD40 is a costimulatory molecule belonging to the TNF receptor superfamily. It is required for the activation of antigen-presenting cells and can polarize TAMs towards a more anti-tumorigenic phenotype. Many cancer cells also express CD40, and high CD40 correlates negatively with overall survival in both low- and high-grade gliomas. A preclinical study showed that the combination of an anti-CD40 antibody and inhibition of CSF1 receptor (CSF1R) signaling reprogrammed TAMs to a more pro-inflammatory phenotype. This combination is now being tested in a phase I clinical trial in solid cancers (NCT02760797). In recurrent glioma, an anti-CD40 antibody is being tested in combination with anti-PD-L1 and D2C7-IT—an immunotoxin conjugated to an anti-EGFR antibody fragment (NCT04547777). In addition, an anti-CD40 antibody is being tested in pediatric CNS tumors (NCT03389802).

NF-κB is a versatile transcription factor, which participates in regulating the inflammatory response. Under normal conditions, NF-κB has been described to support polarization towards M1-like macrophages; however, in a cancer setting, NF-κB signaling in tumor-associated macrophages was shown to inhibit M1 polarization while M2 anti-inflammatory responses were favored. In addition, glioblastoma growth has been shown to require myeloid NF-κB signaling. Moreover, inhibition of NF-κB signaling in myeloid cells leads to M1-like TAM polarization in mouse models of glioblastoma, prostate and pancreatic cancer, which leads to increased infiltration of cytotoxic T cells and decreased tumor growth. Thus, the NF-κB pathway is a potential therapeutic target in different cancers—including glioblastoma—however, more research is needed, and it is yet to be tested in the clinic.

4.3. Decreasing Tumor-Promoting TAMs

As discussed earlier, tumor-promoting TAMs can be either all M2-like TAMs—including both M2-polarized microglia and macrophages—or macrophages only, since some studies suggest that mainly macrophages are pro-tumorigenic, while microglia are more anti-tumorigenic. Most research has focused on targeting the M2-like TAMs since a validated marker for macrophages still awaits. In this regard, it has been speculated to target CD49d, however, more research is necessary to proceed along this line.

CSF1 is released by cancer cells and attracts TAMs, while at the same time polarizes them towards the M2-like phenotype. CSF1R expressed by TAMs is, thus, a target for the depletion of pro-tumorigenic TAMs. CSF1R inhibitors have been tested in numerous clinical trials in solid tumors and acute myeloid leukemia, with the best effect in tenosynovial giant cell tumors, for which it has been FDA approved. Experimentally, there is evidence of anti-tumor effects in glioblastoma models, but in the clinic, there is no effect of CSF1R inhibition in glioblastoma. However, in glioma mouse models, CSF1R inhibitors were shown to sensitize glioma cells to tyrosine kinase inhibitors. Furthermore, two recent studies using glioma and glioblastoma mouse models showed that CSF1R inhibition in combination with radiation prevents the radiation-induced M2-like polarization of TAMs and increases the response to radiation by delaying or preventing recurrent disease. CSF1R inhibitors are also now being tested in clinical trials in combination with standard of care radiation and temozolomide (NCT01790503), as well as in combination with an anti-PD-1 antibody (NCT02829723).

The PD-1/PD-L1 checkpoint axis has been targeted in many cancers after the great success in malignant melanoma. It primarily aims to remove the brake on the anti-tumor cytotoxic T-cell response; however, T cells are scarce and often exhausted in glioblastoma. Both M1- and M2-like TAMs express PD-1 and PD-L1, although M2-like TAMs express them to a higher degree. PD-1 expression has been shown to correlate negatively with TAM phagocytic capacity against cancer cells, and PD-L1 expression may cause inhibition of T cells. In mouse studies of colon cancer and glioma, PD-1/PD-L1 blockade resulted in a decrease in M2-like TAMs, increased TAM phagocytosis, reduced tumor growth and increased survival, independent of T cell presence. Furthermore, PD-1 expression in M2-like TAMs increases with increasing disease stage in patients with colorectal cancer as well as over time in mouse models of colon cancer. The clinical effect of PD-1/PD-L1 blockade in glioblastoma has not been as successful as in other cancers; however, there may be a survival benefit in a neoadjuvant compared to an adjuvant setting using anti-PD-1 in recurrent glioblastoma. A phase 3 clinical trial in recurrent glioblastoma comparing anti-PD-1 with anti-VEGF (Bevacizumab) showed no difference in overall survival, but the anti-PD-1 treated group had more durable responses. In addition, a subgroup of patients with methylated MGMT promoter and no corticosteroid use had increased overall survival. These studies indicate that anti-PD-1 might work in the right setting, and it is now being tested in several clinical trials in combination with other therapies.

One of these combination therapies could be targeting CD73, an ectonucleotidase that together with CD39 converts extracellular ATP into the anti-inflammatory factor adenosine. CD73 is expressed by a subset of TAMs with an immunosuppressive and macrophage-like gene signature. Using single-cell RNA-seq, a CD73high gene signature was derived, and high expression of this signature correlated negatively with overall survival in The Cancer Genome Atlas (TCGA) cohort of glioblastoma patients. In addition, these cells persisted after immune checkpoint therapy. In a glioblastoma mouse model, CD73-/- mice showed improved survival when treated with anti-PD-1 and anti-CTLA-4 compared to untreated mice as well as treated wild-type mice. Depletion of CD73-expressing TAMs could be a potential novel treatment strategy; however, it has not been tested in glioblastoma patients. It is currently being tested in phase I and II clinical trials in several solid cancers, both alone and in combination with immune checkpoint inhibitors.

Like CD73, CD39 is expressed in tumor-associated macrophages, and CD39 inhibition increases the secretion of inflammatory cytokines. In gliomas, CD39 expression increases with increasing disease grade, and it contributes to T cell dysfunction. An anti-CD39 antibody is being tested in a phase I clinical trial in advanced solid tumors (NCT04336098) but has not been tested in glioblastomas.

CD163 is a marker for pro-tumorigenic M2-like TAMs. CD163 expression is positively associated with glioma malignancy grade, and correlates significantly with poor survival in glioblastoma as well as gliomas of all grades. CD163+ TAMs have been shown to impair T cell function in a melanoma mouse model, while depletion of the CD163+ cells resulted in the infiltration of activated T cells and inflammatory monocytes, which led to tumor regression. In addition, CD163+ TAMs isolated from human glioma patients and co-cultured with autologous peripheral T cells decreased the frequency of effector T cells in culture. Subsequent M1-polarization of the TAMs resulted in an increase in effector T cells. Thus, CD163 could be an attractive therapeutic target for depletion of M2-like TAMs. It has, however, not been tested in the clinic.

Another potential new target in glioblastoma is CD204. It is also a marker for M2-like TAMs, and CD204 expression is associated with shorter survival in high-grade gliomas. In addition, the amount of CD204+ TAMs increases with malignancy grade, and CD204 has been shown to be of independent prognostic value in glioblastoma. Currently, the targeting of CD204 has not been tested in clinical trials, but it may be an attractive therapeutic opportunity.

4.4. Combination Therapies and Translational Challenges

Many TAM-targeting therapies are being tested as monotherapies; however, there could be an advantage in combining different treatments. It seems that combining radiation or chemoradiation with TAM targeting—such as inhibition of CXCR4 or CSF1R—can repolarize or deplete the pro-tumorigenic TAMs that infiltrate the tumor after radiation, improving the radiation effect. In addition, PD1 targeting could have a better effect if combined with targeting of, e.g., CD73, which inhibits cytotoxic T cell function.

Selecting patients based on molecular subtypes or gene expression could also aid in getting a better response to a treatment. For example, in the before-mentioned phase 3 trial with anti-PD-1 treatment, the patients with methylated MGMT promoter had improved survival compared to patients with non-methylated MGMT promoter.

Often, preclinical experiments look promising for new targets and therapies; however, there is a poor correlation between existing in vitro and in vivo models and human glioblastoma. In vitro models using cell lines, glioma spheres, tumor organoids or patient-derived cells lack the complete picture of the tumor, both with regard to tumor heterogeneity and subtype, as well as inclusion of the complete TME. In vivo models can give a more complete biological context. Xenograft models—such as the syngeneic, orthotopic GL261 glioma mouse model—have contributed considerably to the understanding of glioma biology; however, even similar experiments investigating anti-PD-1 checkpoint blockade in the GL261 model have shown huge variations. Patient-derived xenografts are also used, and they retain the genetic and histological features of the primary tumor; however, the drawback is that the mouse is often immune deficient to avoid tumor rejection. Today, complex mouse models with humanized immune systems have been made by transplantation of human peripheral blood lymphocytes and/or CD34+ hematopoietic stem cells into immune-deficient mice. These models could potentially contemplate the TME better, but there are still issues to be solved, such as host innate immune responses, incomplete human immune function and limited lifespan. In addition, their value in the glioblastoma setting still needs to be evaluated.

In humans, the blood–brain barrier (BBB) plays a significant role in controlling which cells and drugs enter the brain, and there may be interspecies differences in the BBB in humans and rodents. In addition, while the BBB may be leaky in central parts of human glioblastomas, there are often pronounced and widespread infiltration of the brain parenchyma, where an intact BBB is supposed to be present.

Another critical issue is that even though surgical resection is first-line treatment in glioblastomas, novel therapies are rarely investigated in this context in preclinical models. For TAM-targeting therapies, this is highly relevant, since surgical resection may increase the number of TAMs in recurrent glioblastomas.

To get a better correlation between animal models and human glioblastoma, more studies investigating human glioblastomas and their TME are essential to get a better understanding of the complexity of these tumors. This is possible today, with all the new tools that allow the investigation of gene expression in single cells and the spatial relationship between cells.

5. Single-Cell Omics in Characterization of the Glioblastoma Microenvironment

With recent technological advances in single-cell and spatial sequencing, we are now able to characterize glioblastoma tumors profoundly. The extent of our ability to extract data from glioblastomas has been tested in a recent study, which comprehensively characterized 99 tumors with integrated analysis of single-cell mRNA expression, as well as tumor proteomic, genomic, post-translational modification, and metabolomic data. These methods, which generate large amounts of data with few samples, can be utilized to develop ideas for new therapeutic strategies or to evaluate the effects of TAM-targeting treatments. Using single-cell RNA- or spatial-seq technologies, we can identify changes in cellular or spatial expression patterns and how this potentially affects, e.g., T-cell exhaustion, glioma proliferation, or other markers. Future clinical studies should not only investigate whether drugs targeting the glioblastoma TME are effective, but also elucidate how the drugs affect the TME, comparing naïve and treated tumors in order to potentially explain why treatments are effective or not.

As costs decrease for these technology platforms, the remaining challenge lies mainly in analyzing the enormous amounts of data and deriving information that will benefit patients. These challenges are met by research labs, who produce comprehensible tools that help scientists in analyzing their data through methods—such as principal component analysis, differential gene expression analysis, survival analysis, and unsupervised clustering techniques—to explore and extract biological insights. An example is the user-friendly Seurat; an R-package for the analysis of single-cell data that enables scientists specialized in biology to explore larger datasets, which have previously required a certain level of programming knowledge. Increased simplification and accessibility have been introduced by different companies developing simple, user-friendly platforms for single-cell gene expression studies. These include a full package of, e.g., a droplet-based microfluidics system to capture and barcode single cells in droplets, simple kits for sequencing library preparation, and analysis software to easily process, analyze and visualize the data.

Although many studies have characterized glioblastoma cancer cells, only few studies have investigated and characterized the immune microenvironment. A recent study investigated single-cell mRNA expression profiles in a murine glioma model and found multiple profiles for both microglia and macrophages, with expression patterns indicating functional diversity, while another study investigated ligand–receptor interactions in human single-cell data and found TAMs to express genes involved in cancer cell invasion and angiogenesis. These studies strongly indicate that TAMs cannot be grouped as one subpopulation, but different phenotypes may present themselves as being specifically critical in tumor progression and patient survival with distinct cellular markers.

As most studies investigating single-cell mRNA expression have been limited to data that lack spatial information, the emergence of multiple techniques that preserve cells’ spatial location adds an extra dimension of knowledge. These techniques support research aiming to elucidate the function of TAMs in the TME, and how they affect their neighboring cells.

In recent years, studies have provided an exceptionally in-depth characterization of treatment-naïve glioblastomas, and future studies will likely characterize the effects of newer therapies and guide us in optimizing treatment strategies. These advances may pinpoint treatments that impact human tumors and enhance our understanding of cellular interactions for proposing treatment combinations.

6. Conclusions and Perspectives

The therapeutic targeting of TAMs in glioblastoma has yet to improve patient outcomes. This may be due to our incomplete understanding of the heterogeneity of TAMs and which subpopulations aid tumor growth, but also the insufficiency of TAM targeting as monotherapy.

It is clear that TAMs interact with cancer cells and play a significant role in tumor progression, although our understanding is incomplete. There is a need to dissect the phenotypically and functionally heterogeneous population of TAMs and map their functional roles across tumor anatomic structures. We expect that the near future will bring about several studies elucidating TAM phenotypes and functions using novel single-cell omics and spatial techniques.

A high number of clinical trials targeting TAMs as monotherapies and as combination therapies are currently ongoing and results are pending. These, in combination with more knowledge of TAM biology, might redefine glioblastoma treatment in the future.

References 186

  1. 1.

    Louis D.N., Perry A., Reifenberger G., von Deimling A., Figarella-Branger D., Cavenee W.K., Ohgaki H., Wiestler O.D., Kleihues P., Ellison D.W. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A summary. Acta Neuropathol. 2016;131:803-820.

    Not in our library10.1007/s00401-016-1545-1

  2. 2.

    Tykocki T., Eltayeb M. Ten-year survival in glioblastoma. A systematic review. J. Clin. Neurosci. 2018;54:7-13.

    Not in our library10.1016/j.jocn.2018.05.002

  3. 3.

    Weenink B., French P.J., Smitt P.A.E.S., Debets R., Geurts M. Immunotherapy in glioblastoma: Current shortcomings and future perspectives. Cancers. 2020;12:751.

    Not in our library10.3390/cancers12030751

  4. 4.

    Stupp R., Mason W.P., van den Bent M.J., Weller M., Fisher B., Taphoorn M.J.B., Belanger K., Brandes A.A., Marosi C., Bogdahn U., et al. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N. Engl. J. Med. 2005;352:987-996.

    Not in our library10.1056/nejmoa043330

  5. 5.

    Badie B., Schartner J.M. Flow Cytometric Characterization of Tumor-associated Macrophages in Experimental Gliomas. Neurosurgery. 2000;46:957-962.

    Not in our library10.1097/00006123-200004000-00035

  6. 6.

    Charles N.A., Holland E.C., Gilbertson R., Glass R., Kettenmann H. The brain tumor microenvironment. Glia. 2011;59:1169-1180.

    Not in our library10.1002/glia.21136

  7. 7.

    Sørensen M.D., Dahlrot R.H., Boldt H.B., Hansen S., Kristensen B.W. Tumour-associated microglia/macrophages predict poor prognosis in high-grade gliomas and correlate with an aggressive tumour subtype. Neuropathol. Appl. Neurobiol. 2018;44:185-206.

    Not in our library10.1111/nan.12428

  8. 8.

    Caponegro M.D., Moffitt R.A., Tsirka S.E. Expression of neuropilin-1 is linked to glioma associated microglia and macrophages and correlates with unfavorable prognosis in high grade gliomas. Oncotarget. 2018;9:35655-35665.

    Not in our library10.18632/oncotarget.26273

  9. 9.

    Hambardzumyan D., Gutmann D.H., Kettenmann H., Roesch S., Rapp C., Dettling S., Herold-Mende C. The role of microglia and macrophages in glioma maintenance and progression. Nat. Neurosci. 2015;19:20-27.

    Not in our library10.1038/nn.4185

  10. 10.

    Han S., Ma E., Wang X., Yu C., Dong T., Zhan W., Wei X., Liang G., Feng S. Rescuing defective tumor-infiltrating T-cell proliferation in glioblastoma patients. Oncol. Lett. 2016;12:2924-2929.

    Not in our library10.3892/ol.2016.4944

  11. 11.
    Immune landscapes associated with different glioblastoma molecular subtypes · 2019
    No notice
  12. 12.

    Woroniecka K., Chongsathidkiet P., Rhodin K., Kemeny H., Dechant C., Harrison Farber S., Elsamadicy A.A., Cui X., Koyama S., Jackson C., et al. T-cell exhaustion signatures vary with tumor type and are severe in glioblastoma. Clin. Cancer Res. 2018;24:4175-4186.

    Not in our library10.1158/1078-0432.ccr-17-1846

  13. 13.

    Woroniecka K.I., Rhodin K.E., Chongsathidkiet P., Keith K.A., Fecci P.E. T-Cell dysfunction in glioblastoma: Applying a new framework. Clin. Cancer Res. 2018;24:3792-3802.

    Not in our library10.1158/1078-0432.ccr-18-0047

  14. 14.
    Glioblastoma: Microenvironment and Niche Concept · 2018
    No notice
  15. 15.

    Szulzewsky F., Arora S., de Witte L., Ulas T., Markovic D., Schultze J.L., Holland E.C., Synowitz M., Wolf S.A., Kettenmann H. Human glioblastoma-associated microglia/monocytes express a distinct RNA profile compared to human control and murine samples. Glia. 2016;64:1416-1436.

    Not in our library10.1002/glia.23014

  16. 16.

    Wang Q., Hu B., Hu X., Kim H., Squatrito M., Scarpace L., deCarvalho A.C., Lyu S., Li P., Li Y., et al. Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment. Cancer Cell. 2017;32:42-56.e6.

    Not in our library10.1016/j.ccell.2017.06.003

  17. 17.

    Wei J., Chen P., Gupta P., Ott M., Zamler D., Kassab C., Bhat K.P., Curran M.A., De Groot J.F., Heimberger A.B. Immune biology of glioma-associated macrophages and microglia: Functional and therapeutic implications. Neuro-Oncology. 2020;22:5.

    Not in our library10.1093/neuonc/noz212

  18. 18.

    Bowman R.L., Klemm F., Akkari L., Pyonteck S.M., Sevenich L., Quail D.F., Dhara S., Simpson K., Gardner E.E., Iacobuzio-Donahue C.A., et al. Macrophage Ontogeny Underlies Differences in Tumor-Specific Education in Brain Malignancies. Cell Rep. 2016;17:2445-2459.

    Not in our library10.1016/j.celrep.2016.10.052

  19. 19.

    Wong K., Noubade R., Manzanillo P., Ota N., Foreman O., Hackney J.A., Friedman B.A., Pappu R., Scearce-Levie K., Ouyang W. Mice deficient in NRROS show abnormal microglial development and neurological disorders. Nat. Immunol. 2017;18:633-641.

    Not in our library10.1038/ni.3743

  20. 20.

    Kronenberg G., Uhlemann R., Richter N., Klempin F., Wegner S., Staerck L., Wolf S., Uckert W., Kettenmann H., Endres M., et al. Distinguishing features of microglia- and monocyte-derived macrophages after stroke. Acta Neuropathol. 2018;135:551-568.

    Not in our library10.1007/s00401-017-1795-6

  21. 21.

    Murata Y., Sugimoto K., Yang C., Harada K., Gono R., Harada T., Miyashita Y., Higashisaka K., Katada R., Tanaka J., et al. Activated microglia-derived macrophage-like cells exacerbate brain edema after ischemic stroke correlate with astrocytic expression of aquaporin-4 and interleukin-1 alpha release. Neurochem. Int. 2020;140:104848.

    Not in our library10.1016/j.neuint.2020.104848

  22. 22.

    Müller A., Brandenburg S., Turkowski K., Müller S., Vajkoczy P. Resident microglia, and not peripheral macrophages, are the main source of brain tumor mononuclear cells. Int. J. Cancer. 2015;137:278-288.

    Not in our library10.1002/ijc.29379

  23. 23.

    Bennett M.L., Bennett F.C., Liddelow S.A., Ajami B., Zamanian J.L., Fernhoff N.B., Mulinyawe S.B., Bohlen C.J., Adil A., Tucker A., et al. New tools for studying microglia in the mouse and human CNS. Proc. Natl. Acad. Sci. USA. 2016;113:E1738-E1746.

    Not in our library10.1073/pnas.1525528113

  24. 24.

    Mildner A., Huang H., Radke J., Stenzel W., Priller J. P2Y12 receptor is expressed on human microglia under physiological conditions throughout development and is sensitive to neuroinflammatory diseases. Glia. 2017;65:375-387.

    Not in our library10.1002/glia.23097

  25. 25.
    Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment · 2017
    No notice
  26. 26.

    Venteicher A.S., Tirosh I., Hebert C., Yizhak K., Neftel C., Filbin M.G., Hovestadt V., Escalante L.E., Shaw M.L., Rodman C., et al. Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq. Science. 2017;355:eaai8478.

    Not in our library10.1126/science.aai8478

  27. 27.
    When Immune Cells Turn Bad—Tumor-Associated Microglia/Macrophages in Glioma · 2018
    No notice
  28. 28.

    Mosser D.M., Edwards J.P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 2008;8:958-969.

    Not in our library10.1038/nri2448

  29. 29.

    Gabrusiewicz K., Rodriguez B., Wei J., Hashimoto Y., Healy L.M., Maiti S.N., Thomas G., Zhou S., Wang Q., Elakkad A., et al. Glioblastoma-infiltrated innate immune cells resemble M0 macrophage phenotype. JCI Insight. 2016;1:e85841.

    Not in our library10.1172/jci.insight.85841

  30. 30.

    Chen Z., Feng X., Herting C.J., Garcia V.A., Nie K., Pong W.W., Rasmussen R., Dwivedi B., Seby S., Wolf S.A., et al. Cellular and Molecular Identity of Tumor-Associated Macrophages in Glioblastoma. Cancer Res. 2017;77:2266-2278.

    Not in our library10.1158/0008-5472.can-16-2310

  31. 31.

    Sousa C., Golebiewska A., Poovathingal S.K., Kaoma T., Pires-Afonso Y., Martina S., Coowar D., Azuaje F., Skupin A., Balling R., et al. Single-cell transcriptomics reveals distinct inflammation-induced microglia signatures. EMBO Rep. 2018;19:e46171.

    Not in our library10.15252/embr.201846171

  32. 32.
    Single-cell RNA sequencing reveals functional heterogeneity of glioma-associated brain macrophages · 2021
    No notice
  33. 33.

    Ravi V., Neidert N., Will P., Joseph K., Maier J., Kückelhaus J., Vollmer L., Goeldner J., Behringer S., Scherer F., et al. Lineage and Spatial Mapping of Glioblastoma-associated Immunity. bioRxiv. 2021.

    Not in our library10.1101/2020.06.01.121467

  34. 34.

    Pombo Antunes A.R., Scheyltjens I., Lodi F., Messiaen J., Antoranz A., Duerinck J., Kancheva D., Martens L., De Vlaminck K., Van Hove H., et al. Single-cell profiling of myeloid cells in glioblastoma across species and disease stage reveals macrophage competition and specialization. Nat. Neurosci. 2021;24:595-610.

    Not in our library10.1038/s41593-020-00789-y

  35. 35.

    Puchalski R.B., Shah N., Miller J., Dalley R., Nomura S.R., Yoon J.-G., Smith K.A., Lankerovich M., Bertagnolli D., Bickley K., et al. An anatomic transcriptional atlas of human glioblastoma. Science. 2018;360:660-663.

    Not in our library10.1126/science.aaf2666

  36. 36.

    Tamura R., Ohara K., Sasaki H., Morimoto Y., Kosugi K., Yoshida K., Toda M. Difference in Immunosuppressive Cells Between Peritumoral Area and Tumor Core in Glioblastoma. World Neurosurg. 2018;120:e601-e610.

    Not in our library10.1016/j.wneu.2018.08.133

  37. 37.
    Hypoxia promotes glioma-associated macrophage infiltration via periostin and subsequent M2 polarization by upregulating TGF-beta and M-CSFR · 2016
    No notice
  38. 38.

    Darmanis S., Sloan S.A., Croote D., Mignardi M., Chernikova S., Samghababi P., Zhang Y., Neff N., Kowarsky M., Caneda C., et al. Single-Cell RNA-Seq Analysis of Infiltrating Neoplastic Cells at the Migrating Front of Human Glioblastoma. Cell Rep. 2017;21:1399-1410.

    Not in our library10.1016/j.celrep.2017.10.030

  39. 39.

    Komohara Y., Horlad H., Ohnishi K., Fujiwara Y., Bai B., Nakagawa T., Suzu S., Nakamura H., Kuratsu J., Takeya M. Importance of direct macrophage-tumor cell interaction on progression of human glioma. Cancer Sci. 2012;103:2165-2172.

    Not in our library10.1111/cas.12015

  40. 40.

    Prosniak M., Harshyne L.A., Andrews D.W., Kenyon L.C., Bedelbaeva K., Apanasovich T.V., Heber-Katz E., Curtis M.T., Cotzia P., Hooper D.C. Glioma grade is associated with the accumulation and activity of cells bearing M2 monocyte markers. Clin. Cancer Res. 2013;19:3776-3786.

    Not in our library10.1158/1078-0432.ccr-12-1940

  41. 41.

    Verhaak R.G.W., Hoadley K.A., Purdom E., Wang V., Qi Y., Wilkerson M.D., Miller C.R., Ding L., Golub T., Mesirov J.P., et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17:98-110.

    Not in our library10.1016/j.ccr.2009.12.020

  42. 42.

    Patel A.P., Tirosh I., Trombetta J.J., Shalek A.K., Gillespie S.M., Wakimoto H., Cahill D.P., Nahed B.V., Curry W.T., Martuza R.L., et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014;344:1396-1401.

    Not in our library10.1126/science.1254257

  43. 43.

    Sottoriva A., Spiteri I., Piccirillo S.G.M., Touloumis A., Collins V.P., Marioni J.C., Curtis C., Watts C., Tavaré S. Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc. Natl. Acad. Sci. USA. 2013;110:4009-4014.

    Not in our library10.1073/pnas.1219747110

  44. 44.
    Human Mesenchymal glioblastomas are characterized by an increased immune cell presence compared to Proneural and Classical tumors · 2019
    Not checked
  45. 45.

    Wu A., Wei J., Kong L.Y., Wang Y., Priebe W., Qiao W., Sawaya R., Heimberger A.B. Glioma cancer stem cells induce immunosuppressive macrophages/microglia. Neuro-Oncology. 2010;12:1113-1125.

    Not in our library10.1093/neuonc/noq082

  46. 46.

    Guo X., Pan Y., Gutmann D.H. Genetic and genomic alterations differentially dictate low-grade glioma growth through cancer stem cell-specific chemokine recruitment of T cells and microglia. Neuro-Oncology. 2019;21:1250-1262.

    Not in our library10.1093/neuonc/noz080

  47. 47.

    Lepore F., D’Alessandro G., Antonangeli F., Santoro A., Esposito V., Limatola C., Trettel F. CXCL16/CXCR6 axis drives microglia/macrophages phenotype in physiological conditions and plays a crucial role in glioma. Front. Immunol. 2018;9:2750.

    Not in our library10.3389/fimmu.2018.02750

  48. 48.

    Held-Feindt J., Hattermann K., Müerköster S.S., Wedderkopp H., Knerlich-Lukoschus F., Ungefroren H., Mehdorn H.M., Mentlein R. CX3CR1 promotes recruitment of human glioma-infiltrating microglia/macrophages (GIMs). Exp. Cell Res. 2010;316:1553-1566.

    Not in our library10.1016/j.yexcr.2010.02.018

  49. 49.
    Glioma-derived IL-33 orchestrates an inflammatory brain tumor microenvironment that accelerates glioma progression · 2020
    No notice
  50. 50.

    Wei J., Marisetty A., Schrand B., Gabrusiewicz K., Hashimoto Y., Ott M., Grami Z., Kong L.Y., Ling X., Caruso H., et al. Osteopontin mediates glioblastoma-associated macrophage infiltration and is a potential therapeutic target. J. Clin. Invest. 2019;129:137-149.

    Not in our library10.1172/jci121266

  51. 51.

    Chen P., Zhao D., Li J., Liang X., Li J., Chang A., Henry V.K., Lan Z., Spring D.J., Rao G., et al. Symbiotic Macrophage-Glioma Cell Interactions Reveal Synthetic Lethality in PTEN-Null Glioma. Cancer Cell. 2019;35:868-884.e6.

    Not in our library10.1016/j.ccell.2019.05.003

  52. 52.

    Platten M., Kretz A., Naumann U., Aulwurm S., Egashira K., Isenmann S., Weller M. Monocyte chemoattractant protein-1 increases microglial infiltration and aggressiveness of gliomas. Ann. Neurol. 2003;54:388-392.

    Not in our library10.1002/ana.10679

  53. 53.

    Zhang J., Sarkar S., Cua R., Zhou Y., Hader W., Wee Yong V. A dialog between glioma and microglia that promotes tumor invasiveness through the CCL2/CCR2/interleukin-6 axis. Carcinogenesis. 2012;33:312-319.

    Not in our library10.1093/carcin/bgr289

  54. 54.

    Han J., Alvarez-Breckenridge C.A., Wang Q.E., Yu J. TGF-β signaling and its targeting for glioma treatment. Am. J. Cancer Res. 2015;5:945-955.

    Not in our library

  55. 55.

    Ku M.C., Wolf S.A., Respondek D., Matyash V., Pohlmann A., Waiczies S., Waiczies H., Niendorf T., Synowitz M., Glass R., et al. GDNF mediates glioblastoma-induced microglia attraction but not astrogliosis. Acta Neuropathol. 2013;125:609-620.

    Not in our library10.1007/s00401-013-1079-8

  56. 56.

    Shi J., Huo R., Li N., Li H., Zhai T., Li H., Shen B., Ye J., Fu R., Di W. CYR61, a potential biomarker of tumor inflammatory response in epithelial ovarian cancer microenvironment of tumor progress. BMC Cancer. 2019;19:1140.

    Not in our library10.1186/s12885-019-6321-x

  57. 57.

    Yan S., Liu H., Liu Z., Peng F., Jiang F., Li L., Fu R. CCN1 stimulated the osteoblasts via PTEN/AKT/GSK3β/cyclinD1 signal pathway in Myeloma Bone Disease. Cancer Med. 2020;9:737-744.

    Not in our library10.1002/cam4.2608

  58. 58.

    Uneda A., Kurozumi K., Fujimura A., Fujii K., Ishida J., Shimazu Y., Otani Y., Tomita Y., Hattori Y., Matsumoto Y., et al. Differentiated glioblastoma cells accelerate tumor progression by shaping the tumor microenvironment via CCN1-mediated macrophage infiltration. Acta Neuropathol. Commun. 2021;9:29.

    Not in our library10.1186/s40478-021-01124-7

  59. 59.

    Zhou W., Ke S.Q., Huang Z., Flavahan W., Fang X., Paul J., Wu L., Sloan A.E., McLendon R.E., Li X., et al. Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth. Nat. Cell Biol. 2015;2:170-182.

    Not in our library10.1038/ncb3090

  60. 60.
    Dual Role of WISP1 in maintaining glioma stem cells and tumor-supportive macrophages in glioblastoma · 2020
    No notice
  61. 61.
    Extracellular Vesicles in Glioblastoma Tumor Microenvironment · 2020
    No notice
  62. 62.

    Gabrusiewicz K., Li X., Wei J., Hashimoto Y., Marisetty A.L., Ott M., Wang F., Hawke D., Yu J., Healy L.M., et al. Glioblastoma stem cell-derived exosomes induce M2 macrophages and PD-L1 expression on human monocytes. Oncoimmunology. 2018;7:e1412909.

    Not in our library10.1080/2162402x.2017.1412909

  63. 63.

    De Vrij J., Niek Maas S.L., Kwappenberg K.M.C., Schnoor R., Kleijn A., Dekker L., Luider T.M., De Witte L.D., Litjens M., Van Strien M.E., et al. Glioblastoma-derived extracellular vesicles modify the phenotype of monocytic cells. Int. J. Cancer. 2015;137:1630-1642.

    Not in our library10.1002/ijc.29521

  64. 64.

    Qian M., Wang S., Guo X., Wang J., Zhang Z., Qiu W., Gao X., Chen Z., Xu J., Zhao R., et al. Hypoxic glioma-derived exosomes deliver microRNA-1246 to induce M2 macrophage polarization by targeting TERF2IP via the STAT3 and NF-κB pathways. Oncogene. 2020;39:428-442.

    Not in our library10.1038/s41388-019-0996-y

  65. 65.

    Abels E.R., Maas S.L.N., Nieland L., Wei Z., Cheah P.S., Tai E., Kolsteeg C.J., Dusoswa S.A., Ting D.T., Hickman S., et al. Glioblastoma-Associated Microglia Reprogramming Is Mediated by Functional Transfer of Extracellular miR-21. Cell Rep. 2019;28:3105-3119.e7.

    Not in our library10.1016/j.celrep.2019.08.036

  66. 66.
    Molecular and clinical characterization of CD163 expression via large-scale analysis in glioma · 2019
    Not checked
  67. 67.

    Gürsel D.B., Shin B.J., Burkhardt J.K., Kesavabhotla K., Schlaff C.D., Boockvar J.A. Glioblastoma stem-like cells-biology and therapeutic implications. Cancers. 2011;3:2655-2666.

    Not in our library10.3390/cancers3022655

  68. 68.

    Nørøxe D.S., Poulsen H.S., Lassen U. Hallmarks of glioblastoma: A systematic review. ESMO Open. 2016;1:e000144.

    Not in our library10.1136/esmoopen-2016-000144

  69. 69.

    Chen J., Li Y., Yu T.S., McKay R.M., Burns D.K., Kernie S.G., Parada L.F. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 2012;488:522-526.

    Not in our library10.1038/nature11287

  70. 70.

    Wang R., Chadalavada K., Wilshire J., Kowalik U., Hovinga K.E., Geber A., Fligelman B., Leversha M., Brennan C., Tabar V. Glioblastoma stem-like cells give rise to tumour endothelium. Nature. 2010;468:829-833.

    Not in our library10.1038/nature09624

  71. 71.

    Zhang S., Zhao B.S., Zhou A., Lin K., Zheng S., Lu Z., Chen Y., Sulman E.P., Xie K., Bögler O., et al. m6A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program. Cancer Cell. 2017;31:591-606.e6.

    Not in our library10.1016/j.ccell.2017.02.013

  72. 72.

    Guerra-Rebollo M., Garrido C., Sánchez-Cid L., Soler-Botija C., Meca-Cortés O., Rubio N., Blanco J. Targeting of replicating CD133 and OCT4/SOX2 expressing glioma stem cells selects a cell population that reinitiates tumors upon release of therapeutic pressure. Sci. Rep. 2019;9:9549.

    Not in our library10.1038/s41598-019-46014-0

  73. 73.

    Saadeh F.S., Mahfouz R., Assi H.I. Egfr as a clinical marker in glioblastomas and other gliomas. Int. J. Biol. Markers. 2018;33:22-32.

    Not in our library10.5301/ijbm.5000301

  74. 74.

    Coniglio S.J., Eugenin E., Dobrenis K., Stanley E.R., West B.L., Symons M.H., Segall J.E. Microglial stimulation of glioblastoma invasion involves epidermal growth factor receptor (EGFR) and colony stimulating factor 1 receptor (CSF-1R) signaling. Mol. Med. 2012;18:519-527.

    Not in our library10.2119/molmed.2011.00217

  75. 75.

    Zhou R., Qian D., Hua X., Hu M., Chen H., Wang B. Epidermal Growth Factor (EGF) Promotes Human Malignant Glioma Invasion by Mediating Secretion of Human Cytomegalovirus Infected Monocyte-Derived Macrophages. Precis. Med. 2018;3:1097.

    Not in our library10.14800/pm.1097

  76. 76.

    Erlich R.B., Kahn S.A., Lima F.R.S., Muras A.G., Martins R.A.P., Linden R., Chiarini L.B., Martins V.R., Neto V.M. STI1 promotes glioma proliferation through MAPK and PI3K pathways. Glia. 2007;55:1690-1698.

    Not in our library10.1002/glia.20579

  77. 77.

    Da Fonseca A.C.C., Romão L., Amaral R.F., Assad Kahn S., Lobo D., Martins S., Marcondes de Souza J., Moura-Neto V., Lima F.R.S. Microglial stress inducible protein 1 promotes proliferation and migration in human glioblastoma cells. Neuroscience. 2012;200:130-141.

    Not in our library10.1016/j.neuroscience.2011.10.025

  78. 78.

    Qi L., Yu H., Zhang Y., Zhao D., Lv P., Zhong Y., Xu Y. IL-10 secreted by M2 macrophage promoted tumorigenesis through interaction with JAK2 in glioma. Oncotarget. 2016;7:71673-71685.

    Not in our library10.18632/oncotarget.12317

  79. 79.

    Lu J., Xu Z., Duan H., Ji H., Zhen Z., Li B., Wang H., Tang H., Zhou J., Guo T., et al. Tumor-associated macrophage interleukin-β promotes glycerol-3-phosphate dehydrogenase activation, glycolysis and tumorigenesis in glioma cells. Cancer Sci. 2020;111:1979-1990.

    Not in our library10.1111/cas.14408

  80. 80.

    Bruna A., Darken R.S., Rojo F., Ocaña A., Peñuelas S., Arias A., Paris R., Tortosa A., Mora J., Baselga J., et al. High TGFβ-Smad Activity Confers Poor Prognosis in Glioma Patients and Promotes Cell Proliferation Depending on the Methylation of the PDGF-B Gene. Cancer Cell. 2007;11:147-160.

    Not in our library10.1016/j.ccr.2006.11.023

  81. 81.

    Liu Z., Kuang W., Zhou Q., Zhang Y. TGF-β1 secreted by M2 phenotype macrophages enhances the stemness and migration of glioma cells via the SMAD2/3 signalling pathway. Int. J. Mol. Med. 2018;42:3395-3403.

    Not in our library10.3892/ijmm.2018.3923

  82. 82.

    Sa J.K., Chang N., Lee H.W., Cho H.J., Ceccarelli M., Cerulo L., Yin J., Kim S.S., Caruso F.P., Lee M., et al. Transcriptional regulatory networks of tumor-associated macrophages that drive malignancy in mesenchymal glioblastoma. Genome Biol. 2020;21:216.

    Not in our library10.1186/s13059-020-02140-x

  83. 83.

    Zhang X., Chen L., Dang W.-Q., Cao M.-F., Xiao J.-F., Lv S.-Q., Jiang W.-J., Yao X.-H., Lu H.-M., Miao J.-Y., et al. CCL8 secreted by tumor-associated macrophages promotes invasion and stemness of glioblastoma cells via ERK1/2 signaling. Lab. Investig. 2020;100:619-629.

    Not in our library10.1038/s41374-019-0345-3

  84. 84.

    Wang Y., Liu T., Yang N., Xu S., Li X., Wang D. Hypoxia and macrophages promote glioblastoma invasion by the CCL4-CCR5 axis. Oncol. Rep. 2016;36:3522-3528.

    Not in our library10.3892/or.2016.5171

  85. 85.
    Tumour-associated macrophages secrete pleiotrophin to promote PTPRZ1 signalling in glioblastoma stem cells for tumour growth · 2017
    No notice
  86. 86.

    Fan Y., Ye J., Shen F., Zhu Y., Yeghiazarians Y., Zhu W., Chen Y., Lawton M.T., Young W.L., Yang G.Y. Interleukin-6 stimulates circulating blood-derived endothelial progenitor cell angiogenesis in vitro. J. Cereb. Blood Flow Metab. 2008;28:90-98.

    Not in our library10.1038/sj.jcbfm.9600509

  87. 87.

    Zhu C., Kros J.M., Cheng C., Mustafa D. The contribution of tumor-Associated macrophages in glioma neo-Angiogenesis and implications for anti-Angiogenic strategies. Neuro-Oncology. 2017;19:1435-1446.

    Not in our library10.1093/neuonc/nox081

  88. 88.
    Tumor Development and Angiogenesis in Adult Brain Tumor: Glioblastoma · 2020
    No notice
  89. 89.

    Nijaguna M.B., Patil V., Urbach S., Shwetha S.D., Sravani K., Hegde A.S., Chandramouli B.A., Arivazhagan A., Marin P., Santosh V., et al. Glioblastoma-derived macrophage colony-stimulating factor (MCSF) induces microglial release of insulin-like growth factor-binding protein 1 (IGFBP1) to promote angiogenesis. J. Biol. Chem. 2015;290:23401-23415.

    Not in our library10.1074/jbc.m115.664037

  90. 90.

    Osterberg N., Ferrara N., Vacher J., Gaedicke S., Niedermann G., Weyerbrock A., Doostkam S., Schaefer H.E., Plate K.H., Machein M.R. Decrease of VEGF-A in myeloid cells attenuates glioma progression and prolongs survival in an experimental glioma model. Neuro. Oncol. 2016;18:939-949.

    Not in our library10.1093/neuonc/now005

  91. 91.

    Gilbert M.R., Dignam J.J., Armstrong T.S., Wefel J.S., Blumenthal D.T., Vogelbaum M.A., Colman H., Chakravarti A., Pugh S., Won M., et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N. Engl. J. Med. 2014;370:699-708.

    Not in our library10.1056/nejmoa1308573

  92. 92.

    Wick W., Gorlia T., Bendszus M., Taphoorn M., Sahm F., Harting I., Brandes A.A., Taal W., Domont J., Idbaih A., et al. Lomustine and Bevacizumab in Progressive Glioblastoma. N. Engl. J. Med. 2017;377:1954-1963.

    Not in our library10.1056/nejmoa1707358

  93. 93.

    Goumans M.J., Valdimarsdottir G., Itoh S., Rosendahl A., Sideras P., Ten Dijke P. Balancing the activation state of the endothelium via two distinct TGF-β type I receptors. EMBO J. 2002;21:1743-1753.

    Not in our library10.1093/emboj/21.7.1743

  94. 94.

    Wang X.B., Tian X.Y., Li Y., Li B., Li Z. Elevated expression of macrophage migration inhibitory factor correlates with tumor recurrence and poor prognosis of patients with gliomas. J. Neurooncol. 2012;106:43-45.

    Not in our library10.1007/s11060-011-0640-3

  95. 95.

    Ha W., Sevim-Nalkiran H., Zaman A.M., Matsuda K., Khasraw M., Nowak A.K., Chung L., Baxter R.C., McDonald K.L. Ibudilast sensitizes glioblastoma to temozolomide by targeting Macrophage Migration Inhibitory Factor (MIF). Sci. Rep. 2019;9:2905.

    Not in our library10.1038/s41598-019-39427-4

  96. 96.

    Castro B.A., Flanigan P., Jahangiri A., Hoffman D., Chen W., Kuang R., De Lay M., Yagnik G., Wagner J.R., Mascharak S., et al. Macrophage migration inhibitory factor downregulation: A novel mechanism of resistance to anti-angiogenic therapy. Oncogene. 2017;36:3749-3759.

    Not in our library10.1038/onc.2017.1

  97. 97.

    Mangano K., Mazzon E., Basile M.S., Di Marco R., Bramanti P., Mammana S., Petralia M.C., Fagone P., Nicoletti F. Pathogenic role for macrophage migration inhibitory factor in glioblastoma and its targeting with specific inhibitors as novel tailored therapeutic approach. Oncotarget. 2018;9:17951-17970.

    Not in our library10.18632/oncotarget.24885

  98. 98.

    Guo X., Xu S., Gao X., Wang J., Xue H., Chen Z., Zhang J., Guo X., Qian M., Qiu W., et al. Macrophage migration inhibitory factor promotes vasculogenic mimicry formation induced by hypoxia via CXCR4/AKT/EMT pathway in human glioblastoma cells. Oncotarget. 2017;8:80358-80372.

    Not in our library10.18632/oncotarget.18673

  99. 99.

    Munaut C., Boniver J., Foidart J.M., Deprez M. Macrophage migration inhibitory factor (MIF) expression in human glioblastomas correlates with vascular endothelial growth factor (VEGF) expression. Neuropathol. Appl. Neurobiol. 2002;28:452-460.

    Not in our library10.1046/j.1365-2990.2002.00416.x

  100. 100.

    Zheng P.S., Wen J., Ang L.C., Sheng W., Viloria-Petit A., Wang Y., Wu Y., Kerbel R.S., Yang B.B. Versican/PG-M G3 domain promotes tumor growth and angiogenesis. FASEB J. 2004;18:754-756.

    Not in our library10.1096/fj.03-0545fje

  101. 101.

    Yang W., Yee A.J. Versican V2 isoform enhances angiogenesis by regulating endothelial cell activities and fibronectin expression. FEBS Lett. 2013;587:185-192.

    Not in our library10.1016/j.febslet.2012.11.023

  102. 102.

    Brandenburg S., Müller A., Turkowski K., Radev Y.T., Rot S., Schmidt C., Bungert A.D., Acker G., Schorr A., Hippe A., et al. Resident microglia rather than peripheral macrophages promote vascularization in brain tumors and are source of alternative pro-angiogenic factors. Acta Neuropathol. 2016;131:365-378.

    Not in our library10.1007/s00401-015-1529-6

  103. 103.

    Blank A., Kremenetskaia I., Urbantat R.M., Acker G., Turkowski K., Radke J., Schneider U.C., Vajkoczy P., Brandenburg S. Microglia/macrophages express alternative proangiogenic factors depending on granulocyte content in human glioblastoma. J. Pathol. 2021;253:160-173.

    Not in our library10.1002/path.5569

  104. 104.
    The mode and dynamics of glioblastoma cell invasion into a decellularized tissue-derived extracellular matrix-based three-dimensional tumor model · 2018
    No notice
  105. 105.

    Wu C.Y.-J., Chen C.H., Lin C.Y., Feng L.Y., Lin Y.C., Wei K.C., Huang C.Y., Fang J.Y., Chen P.Y. CCL5 of glioma-associated microglia/macrophages regulates glioma migration and invasion via calcium-dependent matrix metalloproteinase 2. Neuro-Oncology. 2020;22:253-266.

    Not in our library10.1093/neuonc/noz189

  106. 106.

    Markovic D.S., Glass R., Synowitz M., Van Rooijen N., Kettenmann H. Microglia stimulate the invasiveness of glioma cells by increasing the activity of metalloprotease-2. J. Neuropathol. Exp. Neurol. 2005;64:754-762.

    Not in our library10.1097/01.jnen.0000178445.33972.a9

  107. 107.

    Gjorgjevski M., Hannen R., Carl B., Li Y., Landmann E., Buchholz M., Bartsch J.W., Nimsky C. Molecular profiling of the tumor microenvironment in glioblastoma patients: Correlation of microglia/macrophage polarization state with metalloprotease expression profiles and survival. Biosci. Rep. 2019;39:BSR20182361.

    Not in our library10.1042/bsr20182361

  108. 108.

    Yan W., Zhang W., Sun L., Liu Y., You G., Wang Y., Kang C., You Y., Jiang T. Identification of MMP-9 specific microRNA expression profile as potential targets of anti-invasion therapy in glioblastoma multiforme. Brain Res. 2011;1411:108-115.

    Not in our library10.1016/j.brainres.2011.07.002

  109. 109.

    Lakka S.S., Jasti S.L., Gondi C., Boyd D., Chandrasekar N., Dinh D.H., Olivero W.C., Gujrati M., Rao J.S. Downregulation of MMP-9 in ERK-mutated stable transfectants inhibits glioma invasion in vitro. Oncogene. 2002;21:5601-5608.

    Not in our library10.1038/sj.onc.1205646

  110. 110.

    Solga R., Behrens J., Ziemann A., Riou A., Berwanger C., Becker L., Garrett L., de Angelis M.H., Fischer L., Coras R., et al. CRN2 binds to TIMP4 and MMP14 and promotes perivascular invasion of glioblastoma cells. Eur. J. Cell Biol. 2019;98:151046.

    Not in our library10.1016/j.ejcb.2019.151046

  111. 111.

    Wesolowska A., Kwiatkowska A., Slomnicki L., Dembinski M., Master A., Sliwa M., Franciszkiewicz K., Chouaib S., Kaminska B. Microglia-derived TGF-β as an important regulator of glioblastoma invasion—An inhibition of TGF-β-dependent effects by shRNA against human TGF-β type II receptor. Oncogene. 2008;27:918-930.

    Not in our library10.1038/sj.onc.1210683

  112. 112.

    Wick W., Platten M., Weller M. Glioma cell invasion: Regulation of metalloproteinase activity by TGF-β. J. Neurooncol. 2001;53:177-185.

    Not in our library10.1023/a:1012209518843

  113. 113.

    Li R., Li G., Deng L., Liu Q., Dai J., Shen J., Zhang J. IL-6 augments the invasiveness of U87MG human glioblastoma multiforme cells via up-regulation of MMP-2 and fascin-1. Oncol. Rep. 2010;23:1553-1559.

    Not in our library10.3892/or_00000795

  114. 114.
    Tumor cell-released autophagosomes (TRAPs) promote immunosuppression through induction of M2-like macrophages with increased expression of PD-L1 · 2018
    No notice
  115. 115.

    Miyazaki T., Ishikawa E., Matsuda M., Sugii N., Kohzuki H., Akutsu H., Sakamoto N., Takano S., Matsumura A. Infiltration of CD163-positive macrophages in glioma tissues after treatment with anti-PD-L1 antibody and role of PI3Kγ inhibitor as a combination therapy with anti-PD-L1 antibody in in vivo model using temozolomide-resistant murine glioma-initiating cell. Brain Tumor Pathol. 2020;37:41-49.

    Not in our library10.1007/s10014-020-00357-z

  116. 116.

    Bloch O., Crane C.A., Kaur R., Safaee M., Rutkowski M.J., Parsa A.T. Gliomas promote immunosuppression through induction of B7-H1 expression in tumor-associated macrophages. Clin. Cancer Res. 2013;19:3165-3175.

    Not in our library10.1158/1078-0432.ccr-12-3314

  117. 117.

    Ene C.I., Ene C.I., Kreuser S.A., Jung M., Jung M., Zhang H., Arora S., White Moyes K., Szulzewsky F., Barber J., et al. Anti-PD-L1 antibody direct activation of macrophages contributes to a radiation-induced abscopal response in glioblastoma. Neuro-Oncology. 2020;22:639-651.

    Not in our library10.1093/neuonc/noz226

  118. 118.

    Gratas C., Tohma Y., Van Meir E.G., Klein M., Tenan M., Ishii N., Tachibana O., Kleihues P., Ohgaki H. Fas ligond expression in glioblastoma cell lines and primary astrocytic brain tumors. Brain Pathol. 1997;7:863-869.

    Not in our library10.1111/j.1750-3639.1997.tb00889.x

  119. 119.

    Badie B., Schartner J., Prabakaran S., Paul J., Vorpahl J. Expression of Fas ligand by microglia: Possible role in glioma immune evasion. J. Neuroimmunol. 2001;120:19-24.

    Not in our library10.1016/s0165-5728(01)00361-7

  120. 120.

    Chang A.L., Miska J., Wainwright D.A., Dey M., Rivetta C.V., Yu D., Kanojia D., Pituch K.C., Qiao J., Pytel P., et al. CCL2 produced by the glioma microenvironment is essential for the recruitment of regulatory t cells and myeloid-derived suppressor cells. Cancer Res. 2016;76:5671-5682.

    Not in our library10.1158/0008-5472.can-16-0144

  121. 121.

    Wagner S., Czub S., Greif M., Vince G.H., Süss N., Kerkau S., Rieckmann P., Roggendorf W., Roosen K., Tonn J.C. Microglial/macrophage expression of interleukin 10 in human glioblastomas. Int. J. Cancer. 1999;82:12-16.

    Not in our library10.1002/(sici)1097-0215(19990702)82:1<12::aid-ijc3>3.0.co;2-o

  122. 122.

    Hattermann K., Sebens S., Helm O., Schmitt A.D., Mentlein R., Mehdorn H.M., Held-Feindt J. Chemokine expression profile of freshly isolated human glioblastoma- associated macrophages/microglia. Oncol. Rep. 2014;32:270-276.

    Not in our library10.3892/or.2014.3214

  123. 123.

    Thomas D.A., Massagué J. TGF-β directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell. 2005;8:369-380.

    Not in our library10.1016/j.ccr.2005.10.012

  124. 124.

    Sato T., Terai M., Tamura Y., Alexeev V., Mastrangelo M.J., Selvan S.R. Interleukin 10 in the tumor microenvironment: A target for anticancer immunotherapy. Immunol. Res. 2011;51:170-182.

    Not in our library10.1007/s12026-011-8262-6

  125. 125.

    Holmes B., Benavides-Serrato A., Freeman R.S., Landon K.A., Bashir T., Nishimura R.N., Gera J. MTORC2/AKT/HSF1/HuR constitute a feed-forward loop regulating Rictor expression and tumor growth in glioblastoma. Oncogene. 2018;37:732-743.

    Not in our library10.1038/onc.2017.360

  126. 126.

    Wang J., Leavenworth J.W., Hjelmeland A.B., Smith R., Patel N., Borg B., Si Y., King P.H. Deletion of the RNA regulator HuR in tumor-associated microglia and macrophages stimulates anti-tumor immunity and attenuates glioma growth. Glia. 2019;67:2424-2439.

    Not in our library10.1002/glia.23696

  127. 127.

    Kioi M., Vogel H., Schultz G., Hoffman R.M., Harsh G.R., Brown J.M. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J. Clin. Invest. 2010;120:694-705.

    Not in our library10.1172/jci40283

  128. 128.

    Brown J.M., Thomas R., Nagpal S., Recht L. Macrophage exclusion after radiation therapy (MERT): A new and effective way to increase the therapeutic ratio of radiotherapy. Radiother. Oncol. 2020;144:159-164.

    Not in our library10.1016/j.radonc.2019.11.020

  129. 129.

    Akkari L., Bowman R.L., Tessier J., Klemm F., Handgraaf S.M., de Groot M., Quail D.F., Tillard L., Gadiot J., Huse J.T., et al. Dynamic changes in glioma macrophage populations after radiotherapy reveal CSF-1R inhibition as a strategy to overcome resistance. Sci. Transl. Med. 2020;12:eaaw7843.

    Not in our library10.1126/scitranslmed.aaw7843

  130. 130.

    Leblond M.M., Pérès E.A., Helaine C., Gérault A.N., Moulin D., Anfray C., Divoux D., Petit E., Bernaudin M., Valable S. M2 macrophages are more resistant than M1 macrophages following radiation therapy in the context of glioblastoma. Oncotarget. 2017;8:72597-72612.

    Not in our library10.18632/oncotarget.19994

  131. 131.

    Bhat K.P.L., Balasubramaniyan V., Vaillant B., Ezhilarasan R., Hummelink K., Hollingsworth F., Wani K., Heathcock L., James J.D., Goodman L.D., et al. Mesenchymal differentiation mediated by NF-κB promotes radiation resistance in glioblastoma. Cancer Cell. 2013;24:331-346.

    Not in our library10.1016/j.ccr.2013.08.001

  132. 132.

    Pienta K.J., Machiels J.-P., Schrijvers D., Alekseev B., Shkolnik M., Crabb S.J., Li S., Seetharam S., Puchalski T.A., Takimoto C., et al. Phase 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer. Investig. New Drugs. 2013;31:760-768.

    Not in our library10.1007/s10637-012-9869-8

  133. 133.

    Brana I., Calles A., LoRusso P.M., Yee L.K., Puchalski T.A., Seetharam S., Zhong B., de Boer C.J., Tabernero J., Calvo E. Carlumab, an anti-C-C chemokine ligand 2 monoclonal antibody, in combination with four chemotherapy regimens for the treatment of patients with solid tumors: An open-label, multicenter phase 1b study. Target. Oncol. 2015;10:111-123.

    Not in our library10.1007/s11523-014-0320-2

  134. 134.

    Nywening T.M., Wang-Gillam A., Sanford D.E., Belt B.A., Panni R.Z., Cusworth B.M., Toriola A.T., Nieman R.K., Worley L.A., Yano M., et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: A single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol. 2016;17:651-662.

    Not in our library10.1016/s1470-2045(16)00078-4

  135. 135.

    Thomas R.P., Nagpal S., Iv M., Soltys S.G., Bertrand S., Pelpola J.S., Ball R., Yang J., Sundaram V., Lavezo J., et al. Macrophage exclusion after radiation therapy (MERT): A First in Human Phase I/II Trial using a CXCR4 Inhibitor in Glioblastoma. Clin. Cancer Res. 2019;25:6948-6957.

    Not in our library10.1158/1078-0432.ccr-19-1421

  136. 136.

    Lee E.Q., Duda D.G., Muzikansky A., Gerstner E.R., Kuhn J.G., Reardon D.A., Nayak L., Norden A.D., Doherty L., LaFrankie D., et al. Phase I and biomarker study of plerixafor and bevacizumab in recurrent high-grade glioma. Clin. Cancer Res. 2018;24:4643-4649.

    Not in our library10.1158/1078-0432.ccr-18-1025

  137. 137.

    Sikic B.I., Lakhani N., Patnaik A., Shah S.A., Chandana S.R., Rasco D., Colevas A.D., O’Rourke T., Narayanan S., Papadopoulos K., et al. First-in-human, first-in-class phase i trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers. J. Clin. Oncol. 2019;37:946-953.

    Not in our library10.1200/jco.18.02018

  138. 138.

    Grégoire H., Roncali L., Rousseau A., Chérel M., Delneste Y., Jeannin P., Hindré F., Garcion E. Targeting Tumor Associated Macrophages to Overcome Conventional Treatment Resistance in Glioblastoma. Front. Pharmacol. 2020;11:368.

    Not in our library10.3389/fphar.2020.00368

  139. 139.

    Adams S., Kozhaya L., Martiniuk F., Meng T.C., Chiriboga L., Liebes L., Hochman T., Shuman N., Axelrod D., Speyer J., et al. Topical TLR7 agonist imiquimod can induce immune-mediated rejection of skin metastases in patients with breast cancer. Clin. Cancer Res. 2012;18:6748-6757.

    Not in our library10.1158/1078-0432.ccr-12-1149

  140. 140.

    Achyut B.R., Angara K., Jain M., Borin T.F., Rashid M.H., Iskander A.S.M., Ara R., Kolhe R., Howard S., Venugopal N., et al. Canonical NFκB signaling in myeloid cells is required for the glioblastoma growth. Sci. Rep. 2017;7:13754.

    Not in our library10.1038/s41598-017-14079-4

  141. 141.

    Barberi T., Martin A., Suresh R., Barakat D.J., Harris-Bookman S., Drake C.G., Lim M., Friedman A.D. Absence of host NF-κB p50 induces murine glioblastoma tumor regression, increases survival, and decreases T-cell induction of tumor-associated macrophage M2 polarization. Cancer Immunol. Immunother. 2018;67:1491-1503.

    Not in our library10.1007/s00262-018-2184-2

  142. 142.

    Suresh R., Barakat D.J., Barberi T., Zheng L., Jaffee E., Pienta K.J., Friedman A.D. NF-κB p50-deficient immature myeloid cell (p50-IMC) adoptive transfer slows the growth of murine prostate and pancreatic ductal carcinoma. J. Immunother. Cancer. 2020;8:e000244.

    Not in our library10.1136/jitc-2019-000244

  143. 143.

    Tap W.D., Wainberg Z.A., Anthony S.P., Ibrahim P.N., Zhang C., Healey J.H., Chmielowski B., Staddon A.P., Cohn A.L., Shapiro G.I., et al. Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor. N. Engl. J. Med. 2015;373:428-437.

    Not in our library10.1056/nejmoa1411366

  144. 144.

    Butowski N., Colman H., De Groot J.F., Omuro A.M., Nayak L., Wen P.Y., Cloughesy T.F., Marimuthu A., Haidar S., Perry A., et al. Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: An Ivy Foundation Early Phase Clinical Trials Consortium phase II study. Neuro. Oncol. 2016;18:557-564.

    Not in our library10.1093/neuonc/nov245

  145. 145.

    Pyonteck S.M., Akkari L., Schuhmacher A.J., Bowman R.L., Sevenich L., Quail D.F., Olson O.C., Quick M.L., Huse J.T., Teijeiro V., et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 2013;19:1264-1272.

    Not in our library10.1038/nm.3337

  146. 146.

    Almahariq M.F., Quinn T.J., Kesarwani P., Kant S., Miller C.R., Chinnaiyan P. Inhibition of colony-stimulating factor-1 receptor enhances the efficacy of radiotherapy and reduces immune suppression in glioblastoma. In Vivo. 2021;35:119-129.

    Not in our library10.21873/invivo.12239

  147. 147.

    Cloughesy T.F., Mochizuki A.Y., Orpilla J.R., Hugo W., Lee A.H., Davidson T.B., Wang A.C., Ellingson B.M., Rytlewski J.A., Sanders C.M., et al. Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat. Med. 2019;25:477-486.

    Not in our library10.1038/s41591-018-0337-7

  148. 148.

    Reardon D.A., Brandes A.A., Omuro A., Mulholland P., Lim M., Wick A., Baehring J., Ahluwalia M.S., Roth P., Bähr O., et al. Effect of Nivolumab vs Bevacizumab in Patients with Recurrent Glioblastoma: The CheckMate 143 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020;6:1003-1010.

    Not in our library10.1001/jamaoncol.2020.1024

  149. 149.

    Khasraw M., Reardon D.A., Weller M., Sampson J.H. PD-1 Inhibitors: Do they have a Future in the Treatment of Glioblastoma? Clin. Cancer Res. 2020;26:5287-5296.

    Not in our library10.1158/1078-0432.ccr-20-1135

  150. 150.

    Goswami S., Walle T., Cornish A.E., Basu S., Anandhan S., Fernandez I., Vence L., Blando J., Zhao H., Yadav S.S., et al. Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma. Nat. Med. 2020;26:39-46.

    Not in our library10.1038/s41591-019-0694-x

  151. 151.

    Ghalamfarsa G., Kazemi M.H., Raoofi Mohseni S., Masjedi A., Hojjat-Farsangi M., Azizi G., Yousefi M., Jadidi-Niaragh F. CD73 as a potential opportunity for cancer immunotherapy. Expert Opin. Ther. Targets. 2019;23:127-142.

    Not in our library10.1080/14728222.2019.1559829

  152. 152.

    Takenaka M.C., Gabriely G., Rothhammer V., Mascanfroni I.D., Wheeler M.A., Chao C.C., Gutiérrez-Vázquez C., Kenison J., Tjon E.C., Barroso A., et al. Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39. Nat. Neurosci. 2019;22:729-740.

    Not in our library10.1038/s41593-019-0370-y

  153. 153.

    Etzerodt A., Tsalkitzi K., Maniecki M., Damsky W., Delfini M., Baudoin E., Moulin M., Bosenberg M., Graversen J.H., Auphan-Anezin N., et al. Specific targeting of CD163+ TAMs mobilizes inflammatory monocytes and promotes T cell-mediated tumor regression. J. Exp. Med. 2019;216:2394-2411.

    Not in our library10.1084/jem.20182124

  154. 154.

    Yuan Y., Zhao Q., Zhao S., Zhang P., Zhao H., Li Z., Du Y., Tian X., Lu J. Characterization of transcriptome profile and clinical features of a novel immunotherapy target CD204 in diffuse glioma. Cancer Med. 2019;8:3811-3821.

    Not in our library10.1002/cam4.2312

  155. 155.

    Giordano F.A., Link B., Glas M., Herrlinger U., Wenz F., Umansky V., Brown J.M., Herskind C. Targeting the Post-Irradiation Tumor Microenvironment in Glioblastoma via Inhibition of CXCL12. Cancers. 2019;11:272.

    Not in our library10.3390/cancers11030272

  156. 156.

    Stupp R., Hegi M.E., Mason W.P., van den Bent M.J., Taphoorn M.J., Janzer R.C., Ludwin S.K., Allgeier A., Fisher B., Belanger K., et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459-466.

    Not in our library10.1016/s1470-2045(09)70025-7

  157. 157.

    Willingham S.B., Volkmer J.-P., Gentles A.J., Sahoo D., Dalerba P., Mitra S.S., Wang J., Contreras-Trujillo H., Martin R., Cohen J.D., et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc. Natl. Acad. Sci. USA. 2012;109:6662-6667.

    Not in our library10.1073/pnas.1121623109

  158. 158.

    Zhu H., Leiss L., Yang N., Rygh C.B., Mitra S.S., Cheshier S.H., Weissman I.L., Huang B., Miletic H., Bjerkvig R., et al. Surgical debulking promotes recruitment of macrophages and triggers glioblastoma phagocytosis in combination with CD47 blocking immunotherapy. Oncotarget. 2017;8:12145-12157.

    Not in our library10.18632/oncotarget.14553

  159. 159.
    Anti-CD47 Treatment Stimulates Phagocytosis of Glioblastoma by M1 and M2 Polarized Macrophages and Promotes M1 Polarized Macrophages In Vivo · 2016
    No notice
  160. 160.

    Ma D., Liu S., Lal B., Wei S., Wang S., Zhan D., Zhang H., Lee R.S., Gao P., Lopez-Bertoni H., et al. Extracellular Matrix Protein Tenascin C Increases Phagocytosis Mediated by CD47 Loss of Function in Glioblastoma. Cancer Res. 2019;79:2697-2708.

    Not in our library10.1158/0008-5472.can-18-3125

  161. 161.
    Microglia are effector cells of CD47-SIRPα antiphagocytic axis disruption against glioblastoma · 2019
    No notice
  162. 162.

    Zhang X., Chen W., Fan J., Wang S., Xian Z., Luan J., Li Y., Wang Y., Nan Y., Luo M., et al. Disrupting CD47-SIRPα axis alone or combined with autophagy depletion for the therapy of glioblastoma. Carcinogenesis. 2018;39:689-699.

    Not in our library10.1093/carcin/bgy041

  163. 163.

    Hsu S.P.C., Chen Y.C., Chiang H.C., Huang Y.C., Huang C.C., Wang H.E., Wang Y.S., Chi K.H. Rapamycin and hydroxychloroquine combination alters macrophage polarization and sensitizes glioblastoma to immune checkpoint inhibitors. J. Neurooncol. 2020;146:417-426.

    Not in our library10.1007/s11060-019-03360-3

  164. 164.
    A toll-like receptor agonist mimicking microbial signal to generate tumor-suppressive macrophages · 2019
    No notice
  165. 165.

    Werner J.-M., Kuhl S., Ulrich K., Krischek B., Stavrinou P., Goldbrunner R., Timmer M. Expression of CD40 Correlates Negatively with Overall and Progression-Free Survival of Low- and High-Grade Gliomas. World Neurosurg. 2019;130:e17-e25.

    Not in our library10.1016/j.wneu.2019.05.112

  166. 166.

    Hoves S., Ooi C.-H., Wolter C., Sade H., Bissinger S., Schmittnaegel M., Ast O., Giusti A.M., Wartha K., Runza V., et al. Rapid activation of tumor-associated macrophages boosts preexisting tumor immunity. J. Exp. Med. 2018;215:859-876.

    Not in our library10.1084/jem.20171440

  167. 167.

    Lawrence T., Natoli G. Transcriptional regulation of macrophage polarization: Enabling diversity with identity. Nat. Rev. Immunol. 2011;11:750-761.

    Not in our library10.1038/nri3088

  168. 168.

    Saccani A., Schioppa T., Porta C., Biswas S.K., Nebuloni M., Vago L., Bottazzi B., Colombo M.P., Mantovani A., Sica A. p50 nuclear factor-κB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance. Cancer Res. 2006;66:11432-11440.

    Not in our library10.1158/0008-5472.can-06-1867

  169. 169.

    Porta C., Rimoldi M., Raes G., Brys L., Ghezzi P., Di Liberto D., Dieli F., Ghisletti S., Natoli G., De Baetselier P., et al. Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor κB. Proc. Natl. Acad. Sci. USA. 2009;106:14978-14983.

    Not in our library10.1073/pnas.0809784106

  170. 170.

    Cho H.R., Jeon H., Park C.K., Park S.H., Choi S.H. Radiogenomics Profiling for Glioblastoma-related Immune Cells Reveals CD49d Expression Correlation with MRI parameters and Prognosis. Sci. Rep. 2018;8:16022.

    Not in our library10.1038/s41598-018-34242-9

  171. 171.

    Kumar S., Ramesh A., Kulkarni A. Targeting macrophages: A novel avenue for cancer drug discovery. Expert Opin. Drug Discov. 2020;15:561-574.

    Not in our library10.1080/17460441.2020.1733525

  172. 172.

    Yan D., Kowal J., Akkari L., Schuhmacher A.J., Huse J.T., West B.L., Joyce J.A. Inhibition of colony stimulating factor-1 receptor abrogates microenvironment-mediated therapeutic resistance in gliomas. Oncogene. 2017;36:6049-6058.

    Not in our library10.1038/onc.2017.261

  173. 173.

    Gordon S.R., Maute R.L., Dulken B.W., Hutter G., George B.M., McCracken M.N., Gupta R., Tsai J.M., Sinha R., Corey D., et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature. 2017;545:495-499.

    Not in our library10.1038/nature22396

  174. 174.

    Rao G., Latha K., Ott M., Sabbagh A., Marisetty A., Ling X., Zamler D., Doucette T.A., Yang Y., Kong L.Y., et al. Anti-PD-1 induces M1 polarization in the glioma microenvironment and exerts therapeutic efficacy in the absence of CD8 cytotoxic T cells. Clin. Cancer Res. 2020;26:4699-4712.

    Not in our library10.1158/1078-0432.ccr-19-4110

  175. 175.

    Moesta A.K., Li X.Y., Smyth M.J. Targeting CD39 in cancer. Nat. Rev. Immunol. 2020;20:739-755.

    Not in our library10.1038/s41577-020-0376-4

  176. 176.

    Cosset É., Weis S.M., Cheresh D.A. Re-thinking the preclinical development of GBM therapeutics. Oncoscience. 2018;5:11-12.

    Not in our library10.18632/oncoscience.396

  177. 177.

    Tritz Z.P., Ayasoufi K., Johnson A.J. Anti-PD-1 checkpoint blockade monotherapy in the orthotopic GL261 glioma model: The devil is in the detail. Neuro-Oncol. Adv. 2021;3:vdab066.

    Not in our library10.1093/noajnl/vdab066

  178. 178.

    De La Rochere P., Guil-Luna S., Decaudin D., Azar G., Sidhu S.S., Piaggio E. Humanized Mice for the Study of Immuno-Oncology. Trends Immunol. 2018;39:748-763.

    Not in our library10.1016/j.it.2018.07.001

  179. 179.

    Allen T.M., Brehm M.A., Bridges S., Ferguson S., Kumar P., Mirochnitchenko O., Palucka K., Pelanda R., Sanders-Beer B., Shultz L.D., et al. Humanized immune system mouse models: Progress, challenges and opportunities. Nat. Immunol. 2019;20:770-774.

    Not in our library10.1038/s41590-019-0416-z

  180. 180.

    Sarkaria J.N., Hu L.S., Parney I.F., Pafundi D.H., Brinkmann D.H., Laack N.N., Giannini C., Burns T.C., Kizilbash S.H., Laramy J.K., et al. Is the blood-brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data. Neuro-Oncology. 2018;20:184-191.

    Not in our library10.1093/neuonc/nox175

  181. 181.

    Wang L.B., Karpova A., Gritsenko M.A., Kyle J.E., Cao S., Li Y., Rykunov D., Colaprico A., Rothstein J.H., Hong R., et al. Proteogenomic and metabolomic characterization of human glioblastoma. Cancer Cell. 2021;39:509-528.e20.

    Not in our library10.1016/j.ccell.2021.01.006

  182. 182.

    Stuart T., Butler A., Hoffman P., Hafemeister C., Papalexi E., Mauck W.M., Hao Y., Stoeckius M., Smibert P., Satija R. Comprehensive Integration of Single-Cell Data. Cell. 2019;177:1888-1902.e21.

    Not in our library10.1016/j.cell.2019.05.031

  183. 183.

    Yasen A., Aini A., Wang H., Li W., Zhang C., Ran B., Tuxun T., Maimaitinijiati Y., Shao Y., Aji T., et al. Progress and applications of single-cell sequencing techniques. Infect. Genet. Evol. 2020;80:104198.

    Not in our library10.1016/j.meegid.2020.104198

  184. 184.

    Neftel C., Laffy J., Filbin M.G., Hara T., Shore M.E., Rahme G.J., Richman A.R., Silverbush D., Shaw M.L., Hebert C.M., et al. An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma. Cell. 2019;178:835-849.e21.

    Not in our library10.1016/j.cell.2019.06.024

  185. 185.

    Yuan D., Tao Y., Chen G., Shi T. Systematic expression analysis of ligand-receptor pairs reveals important cell-to-cell interactions inside glioma. Cell Commun. Signal. 2019;17:48.

    Not in our library10.1186/s12964-019-0363-1

  186. 186.

    Kalita-de Croft P., Sadeghi Rad H., Gasper H., O’Byrne K., Lakhani S.R., Kulasinghe A. Spatial profiling technologies and applications for brain cancers. Expert Rev. Mol. Diagn. 2021;21:323-332.

    Not in our library10.1080/14737159.2021.1900735

Cited by papers we hold 2

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.