scholarly journals Expression of FOXP3 in Canine Gliomas: Immunohistochemical Study of Tumor-Infiltrating Regulatory Lymphocytes

2019 ◽  
Vol 79 (2) ◽  
pp. 184-193 ◽  
Author(s):  
Dolors Pi Castro ◽  
Roberto José-López ◽  
Francisco Fernández Flores ◽  
Rosa M Rabanal Prados ◽  
Maria Teresa Mandara ◽  
...  
Keyword(s):  
Immune Cell ◽  
Low Grade ◽  
Similar Distribution ◽  
High Grade ◽  
Human Gliomas ◽  
Forkhead Box ◽  
Astrocytic Gliomas ◽  
The Difference ◽  
Regulatory Lymphocytes ◽  
The Brain

Abstract Dogs develop gliomas with similar histopathological features to human gliomas and share with them the limited success of current therapeutic regimens such as surgery and radiation. The tumor microenvironment in gliomas is influenced by immune cell infiltrates. The present study aims to immunohistochemically characterize the tumor-infiltrating lymphocyte (TIL) population of naturally occurring canine gliomas, focusing on the expression of Forkhead box P3-positive (FOXP3+) regulatory T-cells (Tregs). Forty-three canine gliomas were evaluated immunohistochemically for the presence of CD3+, FOXP3+, and CD20+ TILs. In low-grade gliomas, CD3+ TILs were found exclusively within the tumor tissue. In high-grade gliomas, they were present in significantly higher numbers throughout the tumor and in the brain-tumor junction. CD20+ TILs were rarely found in comparison to CD3+ TILs. FOXP3+ TILs shared a similar distribution with CD3+ TILs. The accumulation of FOXP3+ Tregs within the tumor was more pronounced in astrocytic gliomas than in tumors of oligodendroglial lineage and the difference in expression was significant when comparing low-grade oligodendrogliomas and high-grade astrocytomas. Only high-grade astrocytomas presented FOXP3+ cells with tumoral morphology. In spontaneous canine gliomas, TILs display similar characteristics (density and distribution) as described for human gliomas, supporting the use of the dog as an animal model for translational immunotherapeutic studies.

Immunohistochemical evaluation of immune cell infiltration in canine gliomas

2021 ◽  
pp. 030098582110239
Author(s):  
Gregory A. Krane ◽  
Carly A. O’Dea ◽  
David E. Malarkey ◽  
Andrew D. Miller ◽  
C. Ryan Miller ◽  
...  
Keyword(s):  
Immune Cell ◽  
Cell Infiltration ◽  
Low Grade ◽  
Immune Cell Infiltration ◽  
High Grade ◽  
Forkhead Box ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Formalin Fixed ◽  
Tumor Area

Evasion of the immune response is an integral part of the pathogenesis of glioma. In humans, important mechanisms of immune evasion include recruitment of regulatory T cells (Tregs) and polarization of macrophages toward an M2 phenotype. Canine glioma has a robust immune cell infiltrate that has not been extensively characterized. The purpose of this study was to determine the distribution of immune cells infiltrating spontaneous intracranial canine gliomas. Seventy-three formalin-fixed, paraffin-embedded tumor samples were evaluated using immunohistochemistry for CD3, forkhead box 3 (FOXP3), CD20, Iba1, calprotectin (Mac387), CD163, and indoleamine 2,3-dioxygenase (IDO). Immune cell infiltration was present in all tumors. Low-grade and high-grade gliomas significantly differed in the numbers of FoxP3+ cells, Mac387+ cells, and CD163+ cells ( P = .006, .01, and .01, respectively). Considering all tumors, there was a significant increase in tumor area fraction of CD163 compared to Mac387 ( P < .0001), and this ratio was greater in high-grade tumors than in low-grade tumors ( P = .005). These data warrant further exploration into the roles of macrophage repolarization or Treg interference therapy in canine glioma.

scholarly journals Single-cell RNA Sequencing Reveals Immunosuppressive Myeloid Cell Diversity and Restricted Cytotoxic Effector Cell Trafficking and Activation During Malignant Progression in Glioma

2021 ◽  
Author(s):  
Sakthi Rajendran ◽  
Clayton Peterson ◽  
Alessandro Canella ◽  
Yang Hu ◽  
Amy Gross ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
Immune Cell ◽  
Myeloid Cell ◽  
Malignant Progression ◽  
Low Grade ◽  
Cell Trafficking ◽  
High Grade ◽  
Single Cell Rna Sequencing

Low grade gliomas (LGG) account for about two-thirds of all glioma diagnoses in adolescents and young adults (AYA) and malignant progression of these patients leads to dismal outcomes. Recent studies have shown the importance of the dynamic tumor microenvironment in high-grade gliomas (HGG), yet its role is still poorly understood in low-grade glioma malignant progression. Here, we investigated the heterogeneity of the immune microenvironment using a platelet-derived growth factor (PDGF)-driven RCAS (replication-competent ASLV long terminal repeat with a splice acceptor) glioma model that recapitulates the malignant progression of low to high-grade glioma in humans and also provides a model system to characterize immune cell trafficking and evolution. To illuminate changes in the immune cell landscape during tumor progression, we performed single-cell RNA sequencing on immune cells isolated from animals bearing no tumor (NT), LGG and HGG, with a particular focus on the myeloid cell compartment, which is known to mediate glioma immunosuppression. LGGs demonstrated significantly increased infiltrating T cells, CD4 T cells, CD8 T cells, B cells, and natural killer cells in the tumor microenvironment, whereas HGGs significantly abrogated this infiltration. Our study identified two distinct macrophage clusters in the tumor microenvironment; one cluster appeared to be bone marrow-derived while another was defined by overexpression of Trem2, a marker of tumor associated macrophages. Our data demonstrates that these two distinct macrophage clusters show an immune-activated phenotype (Stat1, Tnf, Cxcl9 and Cxcl10) in LGG which evolves to an immunosuppressive state (Lgals3, Apoc1 and Id2) in HGG that restricts T cell recruitment and activation. We identified CD74 and macrophage migration inhibition factor (MIF) as potential targets for these distinct macrophage populations. Interestingly, these results were mirrored by our analysis of the TCGA dataset, which demonstrated a statistically significant association between CD74 overexpression and decreased overall survival in AYA patients with grade II gliomas. Targeting immunosuppressive myeloid cells and intra-tumoral macrophages within this therapeutic window may ameliorate mechanisms associated with immunosuppression before and during malignant progression.

Immune cell infiltrate differences in pilocytic astrocytoma and glioblastoma: evidence of distinct immunological microenvironments that reflect tumor biology

2011 ◽  
Vol 115 (3) ◽  
pp. 505-511 ◽  
Author(s):  
Isaac Yang ◽  
Seunggu J. Han ◽  
Michael E. Sughrue ◽  
Tarik Tihan ◽  
Andrew T. Parsa
Keyword(s):  
Pilocytic Astrocytoma ◽  
Immune Cell ◽  
Tumor Biology ◽  
Human Leukocyte ◽  
Low Grade ◽  
High Grade ◽  
Cell Infiltrate ◽  
Leukocyte Antigen ◽  
Pilocytic Astrocytomas ◽  
Immune Cell Infiltrate

Object The tumor microenvironment in astrocytomas is composed of a variety of cell types, including infiltrative inflammatory cells that are dynamic in nature, potentially reflecting tumor biology. In this paper the authors demonstrate that characterization of the intratumoral inflammatory infiltrate can distinguish high-grade glioblastoma from low-grade pilocytic astrocytoma. Methods Tumor specimens from ninety-one patients with either glioblastoma or pilocytic astrocytoma were analyzed at the University of California, San Francisco. A systematic neuropathology analysis was performed. All tissue was collected at the time of the initial surgery prior to adjuvant treatment. Immune cell infiltrate not associated with necrosis or hemorrhage was analyzed on serial 4-μm sections. Analysis was performed for 10 consecutive hpfs and in 3 separate regions (total 30 × 0.237 mm2). Using immunohistochemistry for markers of infiltrating cytotoxic T cells (CD8), natural killer cells (CD56), and macrophages (CD68), the inflammatory infiltrates in these tumors were graded quantitatively and classified based on microanatomical location (perivascular vs intratumoral). Control markers included CD3, CD20, and human leukocyte antigen. Results Glioblastomas exhibited significantly higher perivascular (CD8) T-cell infiltration than pilocytic astrocytomas (62% vs 29%, p = 0.0005). Perivascular (49%) and intratumoral (89%; p = 0.004) CD56-positive cells were more commonly associated with glioblastoma. The CD68-positive cells also were more prevalent in the perivascular and intratumoral space in glioblastoma. In the intratumoral space, all glioblastomas exhibited CD68-positive cells compared with 86% of pilocytic astrocytomas (p = 0.0014). Perivascularly, CD68-positive infiltrate was also more prevalent in glioblastoma when compared with pilocytic astrocytoma (97% vs 86%, respectively; p = 0.0003). The CD3-positive, CD20-positive, and human leukocyte antigen-positive infiltrates did not differ between glioblastoma and pilocytic astrocytoma. Conclusions This analysis suggests a significantly distinct immune profile in the microenvironment of high-grade glioblastoma versus low-grade pilocytic astrocytoma. This difference in tumor microenvironment may reflect an important difference in the tumor biology of glioblastoma.

scholarly journals Immuno-Phenotyping of High-Grade Glioma Infiltrating Immune Cells Reveals Grade Specific Differences in Cells of Myeloid Origin

2020 ◽  
Author(s):  
Raksha A. Ganesh ◽  
Jayashree V. Raghavan ◽  
Pranali Sonpatki ◽  
Divya Naik ◽  
Priyanka Arunachalam ◽  
...  
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
High Grade Glioma ◽  
Low Grade ◽  
High Grade ◽  
High Grade Gliomas ◽  
Cell Phenotypes ◽  
Grade Iii

AbstractGliomas are heavily infiltrated with immune cells of myeloid origin. Past studies have shown that high-grade gliomas have a higher proportion of alternatively activated and suppressive myeloid cells when compared to low-grade gliomas, which correlate with poor prognosis. However, the differences in immune cell phenotypes within high-grade gliomas (between grade III and IV) are relatively less explored, and a correlation of phenotypic characteristics between immune cells in the blood and high grade tumors has not been performed. Additionally, myeloid cells of granulocytic origin present in gliomas remain poorly characterized. Herein, we address these questions through phenotypic characterizations of monocytes and neutrophils present in blood and tumors of individuals with glioblastoma (GBM, grade IV) or grade III gliomas. Our data show that CD163 expressing M2 monocytes are present in greater proportions in GBM tissue when compared to grade III glioma tissue. In addition, we observe that neutrophils are highly heterogeneous among individuals with glioma, and a greater proportion of granulocytic myeloid-derived suppressor cells are present in grade III gliomas when compared to GBM. Finally, we show that the expression levels of CD86 and CD63 showed a high correlation between blood and tumor, and suggest that these may be used as possible markers for prognosis.

scholarly journals Prognostic Role of Matrix Metalloproteinase Expression in Meningioma: A Cross-Sectional Study.

2020 ◽  
Author(s):  
Maryam Ahmad Sharifuddin ◽  
Sharifah Emilia Tuan Sharif ◽  
Hasnan Jaafar
Keyword(s):  
Cross Sectional Study ◽  
Low Grade ◽  
High Grade ◽  
Sectional Study ◽  
Cross Sectional ◽  
Who Grade ◽  
Exact Test ◽  
Immunohistochemical Markers ◽  
Chi Squared ◽  
The Difference

Abstract Background: Meningioma is the most common intracranial tumor in adults. In addition to the extent of tumor surgical resection and WHO grade, angiogenesis is a prognostic factor that is influenced by MMP-2. Our study examined the association of these prognostic factors with MMP-2 expression in meningioma. Methods: A cross-sectional study of patients diagnosed with meningioma between January 2008 and December 2017 was conducted. All samples were re-reviewed and subjected to immunohistochemical staining for Ki67, MMP-2, and CD34. Pearson’s chi-squared test and Fisher’s exact test were used to examine the association of MMP-2 expression with the WHO grade and microvascular density (MVD). Results: The study included 99 patients aged 23–75. Most patients were female (73.7%). This study included 85 cases of low-grade meningioma (grade I) and 14 cases of high-grade meningioma (grade II, 11; grade III, 3). The most common subtypes were meningothelial, transitional, and fibroblastic. In total, 62 of 85 patients with low-grade meningioma and 10 of 14 patients with high-grade meningioma exhibited high MMP-2 expression, and the difference in the rates between the groups was not significant. Most patients in this study displayed MVD scores of 1+ (54/99) and 2+ (33/99). Of the 54 patients with an MVD score of 1+, 42 exhibited high MMP-2 expression. MMP-2 was expressed by all patients with meningioma. Conclusion: In the future, more samples are required, in high-grade tumors, to prevent bias, and more specific immunohistochemical markers should be used to evaluate angiogenesis.

scholarly journals P11.49 An electrophysiological signature of glioma infiltration in the ex vivo human brain

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii54-iii54
Author(s):  
A J Kirby ◽  
J P Lavrador ◽  
C Brogna ◽  
F Vergani ◽  
C Chandler ◽  
...  
Keyword(s):  
Human Brain ◽  
Brain Tissue ◽  
Brain Slices ◽  
Glioma Cells ◽  
Low Grade ◽  
Tissue Preparation ◽  
High Grade ◽  
Spontaneous Seizure ◽  
Human Brain Tissue ◽  
The Brain

Abstract BACKGROUND Invading glioma cells affect the physiological function of the peritumoural cortex. This may manifest clinically as seizures. Here, we investigate the effect the invading glioma cells on the electrophysiological signalling of the peritumoral cortex using living human brain tissue donated by people having a craniotomy for glioma resection (REC approval, 18/SW/002). MATERIAL AND METHODS The brain tissue was cut into thin slices, which preserved the architecture of the glioma and the adjacent healthy brain. The brain slices were incubated in 5-aminolevulinic acid to make the glioma cells fluorescent. We observed 5-ALA induced fluorescence in both low-grade and high-grade gliomas. This enabled us to make electrophysiological recordings of brain activity across the boundary between glioma and brain. RESULTS We recorded from brain slices of 5 participants with glioblastoma and 4 participants with oligodendroglioma (WHO grade II - III). Spontaneous “seizure-like” discharges were recorded in brain slices from 5/8 participants (3 GBM, 2 oligodendroglioma) who reported seizures and from one participant (GBM) who had not had any clinical seizures. Further analysis of the electrical discharges revealed that they could be subdivided into two distinct types based on the major frequencies in the discharge. CONCLUSION We concluded that human brain slices from people with either a low-grade or a high-grade glioma can generate spontaneous seizure-like discharges. This electrophysiological signature will be compared to infiltration and grade of the glioma cells in the donated sample. The living human brain tissue preparation gives us a platform to study the mechanisms of tumour-associated seizures and how abnormal neural activity affects glioma growth.

scholarly journals Computer-assisted quantitative analysis of Ki-67 antigen in dysplasia: Associated lesions or masses in ulcerative colitis

2007 ◽  
Vol 64 (11) ◽  
pp. 753-758
Author(s):  
Vesna Zivkovic ◽  
Aleksandar Petrovic ◽  
Biljana Djordjevic ◽  
Vuka Katic ◽  
Jasmina Gligorijevic ◽  
...  
Keyword(s):  
Immunohistochemical Staining ◽  
Staining Intensity ◽  
High Grade Dysplasia ◽  
Computer Assisted ◽  
Low Grade ◽  
High Grade ◽  
Ki 67 ◽  
Associated Lesions ◽  
Low Grade Dysplasia ◽  
The Difference

Background/Aim. The aim of this study was to apply computer- assisted methodology in assessment of Ki-67 positivity in "adenoma-like" dysplasia associated lesions or masses (DALMs), and carcinoma in ulcerative colitis (UC), and to determine a new approach to grading of Ki-67 staining intensity. Methods. Immunohistochemical slides were quantitatively analyzed for estimation of proportion and intensity of Ki-67 positive-stained cells in a total of 50 "adenoma-like" DALMs (27 with low-grade dysplasia and 23 with high-grade dysplasia), and 17 adenocarcinomas associated with UC. The four grades of immunohistochemical staining intensity were established by an automated classification of nuclear optical densities. Results. The Ki-67 labeling index (LI) in low-grade dysplasia was significantly lower than in high-grade dysplasia, and carcinoma (p < 0.001). The Ki-67 LI of carcinomas was not significantly different from the value obtained in highgrade dysplasia (p > 0.05), however having the difference in percentage values of the moderate stained nuclei (p < 0.05). The overall average values of chromogene nuclear optical density, showed statistically significant differences between DALMs and carcinoma (p < 0.05), although not between normal mucosa and low-grade dysplasia (p > 0.05). Conclusion. The obtained results imply, according to the overall percentage of labeled nuclei, that high-grade dysplasia is very close to carcinoma, while there is the difference in the percentage of moderately stained nuclei. We showed that Ki-67 positivity have a different internal distribution which could be useful in analysing these lesions. These findings also, indicate the important biological differences between low-grade dysplasia and carcinoma in UC, and a low proliferative potential of the former. Automated image analysis permits an objective estimation of Ki-67 immunohistochemical staining in UCassociated dysplasia and carcinoma.

scholarly journals The Promising IgSF11 Immune Checkpoint Is Highly Expressed in Advanced Human Gliomas and Associates to Poor Prognosis

2021 ◽  
Vol 10 ◽  
Author(s):  
Amina Ghouzlani ◽  
Soumaya Rafii ◽  
Mehdi Karkouri ◽  
Abdelhakim Lakhdar ◽  
Abdallah Badou
Keyword(s):  
T Cell ◽  
Clinical Outcome ◽  
Immune Checkpoint ◽  
High Grade Glioma ◽  
Immune Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Low Grade ◽  
High Grade ◽  
Human Gliomas ◽  
Poor Overall Survival

Glioma is the most prevalent primary brain tumor. Immune checkpoint blockade has made a great stride in mending patient’s clinical outcome for multiple types of cancers. However, PD-1, CTLA-4, or VEGF blockade exhibited only poor outcome in glioma patients. This study aimed to explore the expression and role of IgSF11, an emerging immune checkpoint and a ligand of VISTA, in human gliomas. IgSF11 mRNA expression was assessed in human glioma patients at different grades using 2 independent cohorts, a set of 52 Moroccan samples, including 20 glioma tissues, 22 PBMC samples taken before and 10 PBMC samples taken after surgery; and a series of 667 patients from TCGA. In parallel, immunohistochemistry was performed to evaluate IgSF11 protein staining. IgSF11 gene expression was significantly upregulated in high grade glioma tissues, compared to low grade. IgSF11 protein also showed a significant expression in low and high-grade gliomas. Interestingly, IgSF11 expression seemed to correlate positively with other critical immune checkpoints such as PD1, PDL-1, VISTA, and surprisingly negatively with CTLA-4. Although, T cell markers appeared higher in advanced gliomas, T cell-produced pro-inflammatory genes showed similar expression levels, highly likely because of the potent immunosuppressive microenvironment. Indeed, increased expression of IgSF11 in advanced human gliomas associated with a poor overall survival. Our data strongly suggest that IgSF11 is an immune checkpoint, which is upregulated in advanced human gliomas and contributes to the immunosuppressive state resulting in a poor clinical outcome in glioma patients. IgSF11 could be considered as a possible promising therapeutic target in advanced human gliomas.

scholarly journals A Review on Brain Tumor Classification Methodologies

2019 ◽  
pp. 346-359 ◽  
Author(s):  
Bichitra Panda ◽  
Chandra Sekhar Panda
Keyword(s):  
Feature Extraction ◽  
Brain Tumor ◽  
Brain Tumors ◽  
Brain Mri ◽  
Tumor Classification ◽  
Low Grade ◽  
High Grade ◽  
Mr Images ◽  
The Brain

Brain tumor is one of the leading disease in the world. So automated identification and classification of tumors are important for diagnosis. Magnetic resonance imaging (MRI)is widely used modality for imaging brain. Brain tumor classification refers to classify the brain MR images as normal or abnormal, benign or malignant, low grade or high grade or types. This paper reviews various techniques used for the classification of brain tumors from MR images. Brain tumor classification can be divided into three phases as preprocessing, feature extraction and classification. As segmentation is not mandatory for classification, hence resides in the first phase. The feature extraction phase also contains feature reduction. DWT is efficient for both preprocessing and feature extraction. Texture analysis based on GLCM gives better features for classification where PCA reduces the feature vector maintaining the accuracy of classification of brain MRI. Shape features are important where segmentation has already been performed. The use of SVM along with appropriate kernel techniques can help in classifying the brain tumors from MRI. High accuracy has been achieved to classify brain MRI as normal or abnormal, benign or malignant and low grade or high grade. But classifying the tumors into more particular types is more challenging.

scholarly journals The Difference of Hypoxia Inducible Factor 2α mRNA Expression in High-Grade and Low-Grade Glioma Tissue

2019 ◽  
Vol 13 (2) ◽  
pp. 29
Author(s):  
Bagus Ramasha Amangku ◽  
Syaiful Ichwan ◽  
Septelia Inawati Wanandi ◽  
Novi Silvia Hardiany
Keyword(s):  
Hypoxia Inducible Factor ◽  
Hypoxic Condition ◽  
High Grade Glioma ◽  
Low Grade ◽  
Lower Grade ◽  
High Grade ◽  
Relative Expression ◽  
Method Of Calculation ◽  
The Difference ◽  
Metastasis Therapy

Background: HIF-2α is a transcription factor in hypoxic condition, and high expression levels of it correlate with the concepts of metastasis, therapy opposition and reduced quality of prognosis in various forms of cancerous growth. Due to the exceedingly infiltrative ability of brain glioma cells, gliomas cannot be completely deteriorated with surgery and the relapse rate is high. This study goal to identify the relative expression of HIF-2α gene in the direction of glioma malignancy and its classification. Methods: Specimens used in this research comprise of 20 glioma samples obtained from glioma patients in Cipto Mangunkusumo Hospital. Relative expression of HIF-2α was measured by utilizing quantitative Real Time-Polymerase Chain Reaction (RT-PCR). Cycle threshold (CT) values were achieved correlated with the amplified DNA, and then the relative expression was attained by using Livak method of calculation. Results: The results produced a greater average of relative expression of HIF-2α in the grade III and IV types (18.64; n=7) rather than in the lower grades (5.68; n=13). However, the data is statistically inconsequential. Conclusions: High-grade glioma tends to express HIF-2α mRNA higher compared to the lower grade. Therefore, it is possible to use HIF-2α as a prognostic marker for glioma- diagnosed patients, although additional experiments need to be performed to strengthen these facts.

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