Dataset Information

Immuno-phenotyping of IDH-mutant grade 3 astrocytoma and IDH-wildtype glioblastoma reveals specific differences in cells of myeloid origin.

ABSTRACT: Gliomas 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 3 and grade 4 or GBM) 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, IDH-wild type) or grade 3 IDH-mutant gliomas. We observe that neutrophils are highly heterogeneous among individuals with glioma, and are different from healthy controls. We also show that CD163 expressing M2 monocytes are present in greater proportions in GBM tissue when compared to grade 3 IDH-mutant glioma tissue, and a larger proportion of granulocytic myeloid-derived suppressor cells are present in grade 3 IDH-mutant gliomas when compared to GBM. Finally, we demonstrate 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.

SUBMITTER: Raghavan JV

PROVIDER: S-EPMC8331013 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Immuno-phenotyping of IDH-mutant grade 3 astrocytoma and IDH-wildtype glioblastoma reveals specific differences in cells of myeloid origin.

Raghavan Jayashree V JV Ganesh Raksha A RA Sonpatki Pranali P Naik Divya D John Arivusudar Everad AE Arunachalam Priyanka P Shah Darshat D P S Hari H Lakshmikantha Akhila A Pillai Shibu S Chandrachari Komal Prasad KP Mariswamappa Kiran K Lale Sathyanarayana S Shah Nameeta N Jhunjhunwala Siddharth S

Oncoimmunology 20210802 1

Gliomas 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 3 and grade 4 or GBM) are relatively less explored, and a correlation of phenotypic characteristics between immune cells in the blood an ...[more]

PMID: 34377594

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Project description:BackgroundThe microvessels area (MVA), derived from microvascular proliferation, is a biomarker useful for high-grade glioma classification. Nevertheless, its measurement is costly, labor-intense, and invasive. Finding radiologic correlations with MVA could provide a complementary non-invasive approach without an extra cost and labor intensity and from the first stage. This study aims to correlate imaging markers, such as relative cerebral blood volume (rCBV), and local MVA in IDH-wildtype glioblastoma, and to propose this imaging marker as useful for astrocytoma grade 4 classification.MethodsData from 73 tissue blocks belonging to 17 IDH-wildtype glioblastomas and 7 blocks from 2 IDH-mutant astrocytomas were compiled from the Ivy GAP database. MRI processing and rCBV quantification were carried out using ONCOhabitats methodology. Histologic and MRI co-registration was done manually with experts' supervision, achieving an accuracy of 88.8% of overlay. Spearman's correlation was used to analyze the association between rCBV and microvessel area. Mann-Whitney test was used to study differences of rCBV between blocks with presence or absence of microvessels in IDH-wildtype glioblastoma, as well as to find differences with IDH-mutant astrocytoma samples.ResultsSignificant positive correlations were found between rCBV and microvessel area in the IDH-wildtype blocks (p < 0.001), as well as significant differences in rCBV were found between blocks with microvascular proliferation and blocks without it (p < 0.0001). In addition, significant differences in rCBV were found between IDH-wildtype glioblastoma and IDH-mutant astrocytoma samples, being 2-2.5 times higher rCBV values in IDH-wildtype glioblastoma samples.ConclusionsThe proposed rCBV marker, calculated from diagnostic MRIs, can detect in IDH-wildtype glioblastoma those regions with microvessels from those without it, and it is significantly correlated with local microvessels area. In addition, the proposed rCBV marker can differentiate the IDH mutation status, providing a complementary non-invasive method for high-grade glioma classification.

Project description:As the progression of low-grade diffuse astrocytomas into grade 4 tumors significantly impacts patient prognosis, a better understanding of this process is of paramount importance for improved patient care. In this project, we analyzed matched IDH-mutant astrocytomas before and after progression to grade 4 from six patients (discovery cohort) with genome-wide sequencing, 21 additional patients with targeted sequencing, and 33 patients from Glioma Longitudinal AnalySiS cohort for validation. The Cancer Genome Atlas data from 595 diffuse gliomas provided supportive information. All patients in our discovery cohort received radiation, all but one underwent chemotherapy, and no patient received temozolomide (TMZ) before progression to grade 4 disease. One case in the discovery cohort exhibited a hypermutation signature associated with the inactivation of the MSH2 and DNMT3A genes. In other patients, the number of chromosomal rearrangements and deletions increased in grade 4 tumors. The cell cycle checkpoint gene CDKN2A, or less frequently RB1, was most commonly inactivated after receiving both chemo- and radiotherapy when compared to other treatment groups. Concomitant activating PDGFRA/MET alterations were detected in tumors that acquired a homozygous CDKN2A deletion. NRG3 gene was significantly downregulated and recurrently altered in progressed tumors. Its decreased expression was associated with poorer overall survival in both univariate and multivariate analysis. We also detected progression-related alterations in RAD51B and other DNA repair pathway genes associated with the promotion of error-prone DNA repair, potentially facilitating tumor progression. In our retrospective analysis of patient treatment and survival timelines (n = 75), the combination of postoperative radiation and chemotherapy (mainly TMZ) outperformed radiation, especially in the grade 3 tumor cohort, in which it was typically given after primary surgery. Our results provide further insight into the contribution of treatment and genetic alterations in cell cycle, growth factor signaling, and DNA repair-related genes to tumor evolution and progression.

Dataset Information

Immuno-phenotyping of IDH-mutant grade 3 astrocytoma and IDH-wildtype glioblastoma reveals specific differences in cells of myeloid origin.

Publications

Immuno-phenotyping of IDH-mutant grade 3 astrocytoma and IDH-wildtype glioblastoma reveals specific differences in cells of myeloid origin.

Similar Datasets

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