Search Results (34)

Gliomas, the most common type of primary brain tumor, are a significant cause of morbidity and mortality worldwide. Glioblastoma, a highly malignant subtype, is particularly common, aggressive, and resistant to treatment. The tumor microenvironment (TME) of gliomas, especially glioblastomas, is characterized by a distinct presence of tumor-associated macrophages (TAMs), which densely infiltrate glioblastomas, a hallmark of these tumors. This macrophage population comprises both tissue-resident microglia as well as macrophages derived from the walls of blood vessels and the blood stream. Ionized calcium-binding adapter molecule 1 (Iba1) and CD163 are established cellular markers that enable the identification and functional characterization of these cells within the TME. This review provides an in-depth examination of the roles of Iba1 and CD163 in malignant gliomas, with a focus on TAM activation, migration, and immunomodulatory functions. Additionally, we will discuss how recent advances in AI-enhanced cell identification and visualization techniques have begun to transform the analysis of TAMs, promising unprecedented precision in their characterization and providing new insights into their roles within the TME. Iba1 and CD163 appear to have both unique and shared roles in glioma pathobiology, and both have the potential to be targeted through different molecular and cellular mechanisms. We discuss the therapeutic potential of Iba1 and CD163 based on available preclinical (experimental) and clinical (human tissue-based) evidence. Full article

Background: Malignant gliomas, and notably glioblastoma, are highly aggressive brain tumors. Understanding the mechanisms underlying their progression is crucial for developing more effective treatments. Recent studies have highlighted the role of microglia and brain macrophages in glioblastoma development, but the specific interactions between these immune cells and glioblastoma stem cells (GSCs) remain unclear. Methods: To address this question, we have utilized AI-assisted cell recognition to investigate the spatial relationship between GSCs expressing high levels of CD276 (B7-H3) and microglia- and bone marrow-derived brain macrophages, respectively. Results: Using PathoFusion, our previously developed open-source AI framework, we were able to map specific immunohistochemical phenotypes at the single-cell level within whole-slide images. This approach enabled us to selectively identify Iba1+ and CD163+ macrophages as well as CD276+ GSCs with high specificity and to study their co-localization. Our analysis suggests a closer association of Iba1+ macrophages with GSCs than between CD163+ macrophages and GSCs in glioblastoma. Conclusions: Our findings provide novel insights into the spatial context of tumor immunity in glioblastoma and point to microglia-GSC interactions as a potential mechanism for tumor progression, especially during diffuse tissue infiltration. These findings have significant implications for our understanding of glioblastoma biology, providing a foundation for a comprehensive analysis of microglia activation phenotypes during glioma development. This, in turn, may lead to new therapeutic strategies targeting the early stages of the immune microenvironment of glioblastoma. Full article

The glioblastoma (GBM) tumor microenvironment consists of a heterogeneous mixture of neoplastic and non-neoplastic cells, including immune cells. Tumor recurrence following standard-of-care therapy results in a rich landscape of inflammatory cells throughout the glioma-infiltrated cortex. Immune cells consisting of glioma-associated macrophages and microglia (GAMMs) overwhelmingly constitute the bulk of the recurrent glioblastoma (rGBM) microenvironment, in comparison to the highly cellular and proliferative tumor microenvironment characteristic of primary GBM. These immune cells dynamically interact within the tumor microenvironment and can contribute to disease progression and therapy resistance while also providing novel targets for emerging immunotherapies. Within these varying contexts, histological-based assessments of immune cells in rGBM, including immunohistochemistry (IHC) and immunofluorescence (IF), offer a critical way to visualize and examine the inflammatory landscape. Here, we exhaustively review the available body of literature on the inflammatory landscape in rGBM as identified through histological-based assessments. We highlight the heterogeneity of immune cells throughout the glioma-infiltrated cortex with a focus on microglia and macrophages, drawing insights from canonical and novel immune-cell histological markers to estimate cell phenotypes and function. Lastly, we discuss opportunities for immunomodulatory treatments aiming to harness the inflammatory landscape in rGBM. Full article

Glioblastoma (GBM), the most aggressive astrocytic glioma, remains a therapeutic challenge despite multimodal approaches. Immunotherapy holds promise, but its efficacy is hindered by the highly immunosuppressive GBM microenvironment. This review underscores the urgent need to comprehend the intricate interactions between glioma and immune cells, shaping the immunosuppressive tumor microenvironment (TME) in GBM. Immunotherapeutic advancements have shown limited success, prompting exploration of immunomodulatory approaches targeting tumor-associated macrophages (TAMs) and microglia, constituting a substantial portion of the GBM TME. Converting protumor M2-like TAMs to antitumor M1-like phenotypes emerges as a potential therapeutic strategy for GBM. The blood–brain barrier (BBB) poses an additional challenge to successful immunotherapy, restricting drug delivery to GBM TME. Research efforts to enhance BBB permeability have mainly focused on small molecules, which can traverse the BBB more effectively than biologics. Despite over 200 clinical trials for GBM, studies on small molecule immunomodulators within the GBM TME are scarce. Developing small molecules with optimal brain penetration and selectivity against immunomodulatory pathways presents a promising avenue for combination therapies in GBM. This comprehensive review discusses various immunomodulatory pathways in GBM progression with a focus on immune checkpoints and TAM-related targets. The exploration of such molecules, with the capacity to selectively target key immunomodulatory pathways and penetrate the BBB, holds the key to unlocking new combination therapy approaches for GBM. Full article

Microglia and macrophages play a major role in glioma immune responses within the glioma microenvironment. We aimed to construct a prognostic prediction model for glioma based on microglia/macrophage-correlated genes. Additionally, we sought to develop a non-invasive radiogenomics approach for risk stratification evaluation. Microglia/macrophage-correlated genes were identified from four single-cell datasets. Hub genes were selected via lasso–Cox regression, and risk scores were calculated. The immunological characteristics of different risk stratifications were assessed, and radiomics models were constructed using corresponding MRI imaging to predict risk stratification. We identified eight hub genes and developed a relevant risk score formula. The risk score emerged as a significant prognostic predictor correlated with immune checkpoints, and a relevant nomogram was drawn. High-risk groups displayed an active microenvironment associated with microglia/macrophages. Furthermore, differences in somatic mutation rates, such as IDH1 missense variant and TP53 missense variant, were observed between high- and low-risk groups. Lastly, a radiogenomics model utilizing five features from magnetic resonance imaging (MRI) T2 fluid-attenuated inversion recovery (Flair) effectively predicted the risk groups under a random forest model. Our findings demonstrate that risk stratification based on microglia/macrophages can effectively predict prognosis and immune functions in glioma. Moreover, we have shown that risk stratification can be non-invasively predicted using an MRI-T2 Flair-based radiogenomics model. Full article

Glioblastoma is a deadly disease, with a mean overall survival of less than 2 years from diagnosis. Recurrence after gross total surgical resection and adjuvant chemo-radiotherapy almost invariably occurs within the so-called peritumoral brain zone (PBZ). The aim of this narrative review is to summarize the most relevant findings about the biological characteristics of the PBZ currently available in the medical literature. The PBZ presents several peculiar biological characteristics. The cellular landscape of this area is different from that of healthy brain tissue and is characterized by a mixture of cell types, including tumor cells (seen in about 30% of cases), angiogenesis-related endothelial cells, reactive astrocytes, glioma-associated microglia/macrophages (GAMs) with anti-inflammatory polarization, tumor-infiltrating lymphocytes (TILs) with an “exhausted” phenotype, and glioma-associated stromal cells (GASCs). From a genomic and transcriptomic point of view, compared with the tumor core and healthy brain tissue, the PBZ presents a “half-way” pattern with upregulation of genes related to angiogenesis, the extracellular matrix, and cellular senescence and with stemness features and downregulation in tumor suppressor genes. This review illustrates that the PBZ is a transition zone with a pre-malignant microenvironment that constitutes the base for GBM progression/recurrence. Understanding of the PBZ could be relevant to developing more effective treatments to prevent GBM development and recurrence. Full article

Optic pathway glioma (OPG) is one of the causes of pediatric visual impairment. Unfortunately, there is as yet no cure for such a disease. Understanding the underlying mechanisms and the potential therapeutic strategies may help to delay the progression of OPG and rescue the visual morbidities. Here, we provide an overview of preclinical OPG studies and the regulatory pathways controlling OPG pathophysiology. We next discuss the role of microenvironmental cells (neurons, T cells, and tumor-associated microglia and macrophages) in OPG development. Last, we provide insight into potential therapeutic strategies for treating OPG and promoting axon regeneration. Full article

The goal of this study was to define the glioma-associated microglia/macrophage (GAM) response and associated molecular landscape in canine oligodendrogliomas. Here, we quantified the intratumoral GAM density of low- and high-grade oligodendrogliomas compared to that of a normal brain, as well as the intratumoral concentration of several known GAM-derived pro-tumorigenic molecules in high-grade oligodendrogliomas compared to that in a normal brain. Our analysis demonstrated marked intra- and intertumoral heterogeneity of GAM infiltration. Correspondingly, we observed significant variability in the intratumoral concentrations of several GAM-associated molecules, unlike what we previously observed in high-grade astrocytomas. However, high-grade oligodendroglioma tumor homogenates (n = 6) exhibited an increase in the pro-tumorigenic molecules hepatocyte growth factor receptor (HGFR) and vascular endothelial growth factor (VEGF), as we observed in high-grade astrocytomas. Moreover, neoplastic oligodendrocytes displayed robust expression of GAL-3, a chimeric galectin implicated in driving immunosuppression in human glioblastoma. While this work identifies shared putative therapeutic targets across canine glioma subtypes (HGFR, GAL-3), it highlights several key differences in the immune landscape. Therefore, a continued effort to develop a comprehensive understanding of the immune microenvironment within each subtype is necessary to inform therapeutic strategies going forward. Full article

Glioblastoma (GBM) is a common and highly malignant primary tumor of the central nervous system in adults. Ever more recent papers are focusing on understanding the role of the tumor microenvironment (TME) in affecting tumorigenesis and the subsequent prognosis. We assessed the impact of macrophages in the TME on the prognosis in patients with recurrent GBM. A PubMed, MEDLINE and Scopus review was conducted to identify all studies dealing with macrophages in the GBM microenvironment from January 2016 to December 2022. Glioma-associated macrophages (GAMs) act critically in enhancing tumor progression and can alter drug resistance, promoting resistance to radiotherapy and establishing an immunosuppressive environment. M1 macrophages are characterized by increased secretion of proinflammatory cytokines, such as IL-1ß, tumor necrosis factor (TNF), IL-27, matrix metalloproteinase (MMPs), CCL2, and VEGF (vascular endothelial growth factor), IGF1, that can lead to the destruction of the tissue. In contrast, M2 is supposed to participate in immunosuppression and tumor progression, which is formed after being exposed to the macrophage M-CSF, IL-10, IL-35 and the transforming growth factor-ß (TGF-β). Because there is currently no standard of care in recurrent GBM, novel identified targeted therapies based on the complex signaling and interactions between the glioma stem cells (GSCs) and the TME, especially resident microglia and bone-marrow-derived macrophages, may be helpful in improving the overall survival of these patients in the near future. Full article

Gliomas are primary malignant brain tumors. These tumors seem to be more and more frequent, not only because of a true increase in their incidence, but also due to the increase in life expectancy of the general population. Among gliomas, malignant gliomas and more specifically glioblastomas (GBM) are a challenge in their diagnosis and treatment. There are few effective therapies for these tumors, and patients with GBM fare poorly, even after aggressive surgery, chemotherapy, and radiation. Over the last decade, it is now appreciated that these tumors are composed of numerous distinct tumoral and non-tumoral cell populations, which could each influence the overall tumor biology and response to therapies. Monocytes have been proved to actively participate in tumor growth, giving rise to the support of tumor-associated macrophages (TAMs). In GBM, TAMs represent up to one half of the tumor mass cells, including both infiltrating macrophages and resident brain microglia. Infiltrating macrophages/monocytes constituted ~ 85% of the total TAM population, they have immune functions, and they can release a wide array of growth factors and cytokines in response to those factors produced by tumor and non-tumor cells from the tumor microenvironment (TME). A brief review of the literature shows that this cell population has been increasingly studied in GBM TME to understand its role in tumor progression and therapeutic resistance. Through the knowledge of its biology and protumoral function, the development of therapeutic strategies that employ their recruitment as well as the modulation of their immunological phenotype, and even the eradication of the cell population, can be harnessed for therapeutic benefit. This revision aims to summarize GBM TME and localization in tumor niches with special focus on TAM population, its origin and functions in tumor progression and resistance to conventional and experimental GBM treatments. Moreover, recent advances on the development of TAM cell targeting and new cellular therapeutic strategies based on monocyte/macrophages recruitment to eradicate GBM are discussed as complementary therapeutics. Full article

Glioblastoma multiforme (GBM) is the most aggressive form of adult brain tumor which is highly resistant to conventional treatment and therapy. Glioma cells are highly motile resulting in infiltrative tumors with poorly defined borders. Another hallmark of GBM is a high degree of tumor macrophage/microglia infiltration. The level of these tumor-associated macrophages/microglia (TAMs) correlates with higher malignancy and poorer prognosis. We previously demonstrated that inhibition of TAM infiltration into glioma tumors with the CSF-1R antagonist pexidartinib (PLX3397) can inhibit glioma cell invasion in-vitro and in-vivo. In this study, we demonstrate an important role for the chemokine receptor CCR1 in mediating microglia/TAM stimulated glioma invasion. Using two structurally distinct CCR1 antagonists, including a novel inhibitor “MG-1-5”, we were able to block microglial activated GL261 glioma cell invasion in a dose dependent manner. Interestingly, treatment of a murine microglia cell line with glioma conditioned media resulted in a strong induction of CCR1 gene and protein expression. This induction was attenuated by inhibition of CSF-1R. In addition, glioma conditioned media treatment of microglia resulted in a rapid upregulation of gene expression of several CCR1 ligands including CCL3, CCL5, CCL6 and CCL9. These data support the existence of tumor stimulated autocrine loop within TAMs which ultimately mediates tumor cell invasion. Full article

A common theme in glioma disease progression is robust infiltration of immune cells within the tumor microenvironment, resulting in a state of chronic inflammation. This disease state is characterized by an abundance of CD68⁺ microglia and CD163⁺ bone marrow-derived macrophages with the greater the percentage of CD163⁺ cells, the poorer the prognosis. These macrophages are “cold,” in that their phenotype is of an alternatively activated state (M0-M2-like) supporting tumor growth rather than being engaged with classically activated, pro-inflammatory, and anti-tumor activities, referred to as “hot”, or M1-like. Herein, we have developed an in vitro approach that uses two human glioma cell lines, T98G and LN-18, which exhibit a variety of differing mutations and characteristics, to demonstrate their disparate effects on differentiated THP-1 macrophages. We first developed an approach to differentiating THP-1 monocytes to macrophages with mixed transcriptomic phenotypes we regard as M0-like macrophages. We then found that supernatants from the two different glioma cell lines induced different gene expression profiles in THP-1 macrophages, suggesting that from patient to patient, gliomas may be considered as different diseases. This study suggests that in addition to standard glioma treatment modalities, transcriptome profiling of the effects of cultured glioma cells on a standard THP-1 macrophage in vitro model may lead to future druggable targets that aim to reprogram tumor-associated macrophages towards an anti-tumor phenotype. Full article

Glioblastoma is the most aggressive brain tumor in adults. Treatment failure is predominantly caused by its high invasiveness and its ability to induce a supportive microenvironment. As part of this, a major role for tumor-associated macrophages/microglia (TAMs) in glioblastoma development was recognized. Phospholipids are important players in various fundamental biological processes, including tumor–stroma crosstalk, and the bioactive lipid sphingosine-1-phosphate (S1P) has been linked to glioblastoma cell proliferation, invasion, and survival. Despite the urgent need for better therapeutic approaches, novel strategies targeting sphingolipids in glioblastoma are still poorly explored. Here, we showed that higher amounts of S1P secreted by glioma cells are responsible for an active recruitment of TAMs, mediated by S1P receptor (S1PR) signaling through the modulation of Rac1/RhoA. This resulted in increased infiltration of TAMs in the tumor, which, in turn, triggered their pro-tumorigenic phenotype through the inhibition of NFkB-mediated inflammation. Gene set enrichment analyses showed that such an anti-inflammatory microenvironment correlated with shorter survival of glioblastoma patients. Inhibition of S1P restored a pro-inflammatory phenotype in TAMs and resulted in increased survival of tumor-bearing mice. Taken together, our results establish a crucial role for S1P in fine-tuning the crosstalk between glioma and infiltrating TAMs, thus pointing to the S1P–S1PR axis as an attractive target for glioma treatment. Full article

Evidence is accumulating that the tumour microenvironment (TME) has a key role in the progression of gliomas. Non-neoplastic cells in addition to the tumour cells are therefore finding increasing attention. Microglia and other glioma-associated macrophages are at the centre of this interest especially in the context of therapeutic considerations. New ideas have emerged regarding the role of microglia and, more recently, blood-derived brain macrophages in glioblastoma (GBM) progression. We are now beginning to understand the mechanisms that allow malignant glioma cells to weaken microglia and brain macrophage defence mechanisms. Surface molecules and cytokines have a prominent role in microglia/macrophage-glioma cell interactions, and we discuss them in detail. The involvement of exosomes and microRNAs forms another focus of this review. In addition, certain microglia and glioma cell pathways deserve special attention. These “synergistic” (we suggest calling them “Janus”) pathways are active in both glioma cells and microglia/macrophages where they act in concert supporting malignant glioma progression. Examples include CCN4 (WISP1)/Integrin α6β1/Akt and CHI3L1/PI3K/Akt/mTOR. They represent attractive therapeutic targets. Full article

Glioblastoma is the most common primary brain tumor, highly aggressive by being proliferative, neovascularized and invasive, heavily infiltrated by immunosuppressive glioma-associated myeloid cells (GAMs), including glioma-associated microglia/macrophages (GAMM) and myeloid-derived suppressor cells (MDSCs). Quantifying GAMs by molecular imaging could support patient selection for GAMs-targeting immunotherapy, drug target engagement and further assessment of clinical response. Magnetic resonance imaging (MRI) and amino acid positron emission tomography (PET) are clinically established imaging methods informing on tumor size, localization and secondary phenomena but remain quite limited in defining tumor heterogeneity, a key feature of glioma resistance mechanisms. The combination of different imaging modalities improved the in vivo characterization of the tumor mass by defining functionally distinct tissues probably linked to tumor regression, progression and infiltration. In-depth image validation on tracer specificity, biological function and quantification is critical for clinical decision making. The current review provides a comprehensive overview of the relevant experimental and clinical data concerning the spatiotemporal relationship between tumor cells and GAMs using PET imaging, with a special interest in the combination of amino acid and translocator protein (TSPO) PET imaging to define heterogeneity and as therapy readouts. Full article