scholarly journals P.047 IDH mutations are associated with pro-inflammatory microglia and macrophages in heterogeneously infiltrated glioblastomas

2018 ◽  
Vol 45 (s2) ◽  
pp. S28-S28
Author(s):  
CC Poon ◽  
R Yang ◽  
T Sheikh ◽  
K Liu ◽  
S Sarkar ◽  
...  
Keyword(s):  
Immune Cells ◽  
Cell Sorting ◽  
Inflammatory Infiltrate ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Cell Surface Markers ◽  
Tumor Surveillance ◽  
Idh Mutations ◽  
Inflammatory Phenotype ◽  
Immunologic Status

Background: CNS innate immune cells, microglia and macrophages (MMs), are the largest component of the inflammatory infiltrate in glioblastoma (GBM). They initially participate in tumor surveillance, but are co-opted by GBM to further angiogenesis and invasion. There are no effective immunotherapies against GBM in part because GBM-associated MMs are not well understood. We hypothesized that the extent and inflammatory phenotype of MM infiltration into GBM is variable between patients. This variability could have important implications on immunotherapy selection and treatment outcomes. Methods: Using automated quantitation of fluorescently labeled human GBMs, flow cytometry/live cell sorting, collection of conditioned GBM-associated MM media, and corroboration with TCGA and previously published scRNA-seq data, we have uncovered there is surprisingly marked variation in the amount of MM infiltration between tumors. Results: MM infiltration can range from almost non-existent, to comprising ~70% of GBM cells. By detecting cell surface markers and secreted cytokines, we determined that a mixture of pro- and anti-inflammatory MMs are found in each tumor. The overall inflammatory phenotype did not depend on the amount of infiltration. Interestingly, IDH-mutant GBM-associated MMs are more pro-inflammatory and less heterogeneous than IDH-wildtype GBMs. Conclusions: Taken together, the highly variable immunologic status of GBMs suggests the success of immunotherapies hinges on selecting appropriately vulnerable tumors.

scholarly journals Neuroimmunomodulatory Properties of Flavonoids and Derivates: A Potential Action as Adjuvants for the Treatment of Glioblastoma

Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 116
Author(s):  
Ravena Pereira do Nascimento ◽  
Balbino Lino dos Santos ◽  
Jéssika Alves Oliveira Amparo ◽  
Janaina Ribeiro Pereira Soares ◽  
Karina Costa da Silva ◽  
...  
Keyword(s):  
Immune Cells ◽  
Stromal Cells ◽  
Tumor Invasion ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Pharmacological Properties ◽  
C6 Cells ◽  
Perivascular Niche ◽  
Tumor Surveillance ◽  
Scientific Attention

Glioblastomas (GBMs) are tumors that have a high ability to migrate, invade and proliferate in the healthy tissue, what greatly impairs their treatment. These characteristics are associated with the complex microenvironment, formed by the perivascular niche, which is also composed of several stromal cells including astrocytes, microglia, fibroblasts, pericytes and endothelial cells, supporting tumor progression. Further microglia and macrophages associated with GBMs infiltrate the tumor. These innate immune cells are meant to participate in tumor surveillance and eradication, but they become compromised by GBM cells and exploited in the process. In this review we discuss the context of the GBM microenvironment together with the actions of flavonoids, which have attracted scientific attention due to their pharmacological properties as possible anti-tumor agents. Flavonoids act on a variety of signaling pathways, counteracting the invasion process. Luteolin and rutin inhibit NFκB activation, reducing IL-6 production. Fisetin promotes tumor apoptosis, while inhibiting ADAM expression, reducing invasion. Naringenin reduces tumor invasion by down-regulating metalloproteinases expression. Apigenin and rutin induce apoptosis in C6 cells increasing TNFα, while decreasing IL-10 production, denoting a shift from the immunosuppressive Th2 to the Th1 profile. Overall, flavonoids should be further exploited for glioma therapy.

scholarly journals Single-Cell RNA Sequencing Identifies Candidate Renal Resident Macrophage Gene Expression Signatures across Species

2019 ◽  
Vol 30 (5) ◽  
pp. 767-781 ◽  
Author(s):  
Kurt A. Zimmerman ◽  
Melissa R. Bentley ◽  
Jeremie M. Lever ◽  
Zhang Li ◽  
David K. Crossman ◽  
...  
Keyword(s):  
Immune Cells ◽  
Kidney Tissue ◽  
Human Kidney ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Cell Surface Markers ◽  
Resident Macrophage ◽  
Single Cell Rna Sequencing ◽  
Macrophage Populations ◽  
Multiple Species

BackgroundResident macrophages regulate homeostatic and disease processes in multiple tissues, including the kidney. Despite having well defined markers to identify these cells in mice, technical limitations have prevented identification of a similar cell type across species. The inability to identify resident macrophage populations across species hinders the translation of data obtained from animal model to human patients.MethodsAs an entry point to determine novel markers that could identify resident macrophages across species, we performed single-cell RNA sequencing (scRNAseq) analysis of all T and B cell–negative CD45+ innate immune cells in mouse, rat, pig, and human kidney tissue.ResultsWe identified genes with enriched expression in mouse renal resident macrophages that were also present in candidate resident macrophage populations across species. Using the scRNAseq data, we defined a novel set of possible cell surface markers (Cd74 and Cd81) for these candidate kidney resident macrophages. We confirmed, using parabiosis and flow cytometry, that these proteins are indeed enriched in mouse resident macrophages. Flow cytometry data also indicated the existence of a defined population of innate immune cells in rat and human kidney tissue that coexpress CD74 and CD81, suggesting the presence of renal resident macrophages in multiple species.ConclusionsBased on transcriptional signatures, our data indicate that there is a conserved population of innate immune cells across multiple species that have been defined as resident macrophages in the mouse. Further, we identified potential cell surface markers to allow for future identification and characterization of this candidate resident macrophage population in mouse, rat, and pig translational studies.

scholarly journals Tumor-Associated Macrophage Status in Cancer Treatment

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1987 ◽  
Author(s):  
Anna Maria Malfitano ◽  
Simona Pisanti ◽  
Fabiana Napolitano ◽  
Sarah Di Somma ◽  
Rosanna Martinelli ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Immune Cells ◽  
Indirect Effects ◽  
Poor Prognosis ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Tumor Associated Macrophage ◽  
Inflammatory Phenotype ◽  
Anti Inflammatory ◽  
Activation Status

Tumor-associated macrophages (TAMs) represent the most abundant innate immune cells in tumors. TAMs, exhibiting anti-inflammatory phenotype, are key players in cancer progression, metastasis and resistance to therapy. A high TAM infiltration is generally associated with poor prognosis, but macrophages are highly plastic cells that can adopt either proinflammatory/antitumor or anti-inflammatory/protumor features in response to tumor microenvironment stimuli. In the context of cancer therapy, many anticancer therapeutics, apart from their direct effect on tumor cells, display different effects on TAM activation status and density. In this review, we aim to evaluate the indirect effects of anticancer therapies in the modulation of TAM phenotypes and pro/antitumor activity.

scholarly journals Microglial translational profiling reveals a convergent APOE pathway from aging, amyloid, and tau

2018 ◽  
Vol 215 (9) ◽  
pp. 2235-2245 ◽  
Author(s):  
Silvia S. Kang ◽  
Mark T.W. Ebbert ◽  
Kelsey E. Baker ◽  
Casey Cook ◽  
Xuewei Wang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disease ◽  
Immune Cells ◽  
Cell Sorting ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Potential Mechanism ◽  
The Brain

Alzheimer’s disease (AD) is an age-associated neurodegenerative disease characterized by amyloidosis, tauopathy, and activation of microglia, the brain resident innate immune cells. We show that a RiboTag translational profiling approach can bypass biases due to cellular enrichment/cell sorting. Using this approach in models of amyloidosis, tauopathy, and aging, we revealed a common set of alterations and identified a central APOE-driven network that converged on CCL3 and CCL4 across all conditions. Notably, aged females demonstrated a significant exacerbation of many of these shared transcripts in this APOE network, revealing a potential mechanism for increased AD susceptibility in females. This study has broad implications for microglial transcriptomic approaches and provides new insights into microglial pathways associated with different pathological aspects of aging and AD.

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