Dataset Information

Expression profiling of immune inhibitory Siglecs and their ligands in patients with glioma.

ABSTRACT: Gliomas appear to be highly immunosuppressive tumors, with a strong myeloid component. This includes MDSCs, which are a heterogeneous, immature myeloid cell population expressing myeloid markers Siglec-3 (CD33) and CD11b and lacking markers of mature myeloid cells including MHC II. Siglec-3 is a member of the sialic acid-binding immunoglobulin-like lectin (Siglec) family and has been suggested to promote MDSC expansion and suppression. Siglecs form a recently defined family of receptors with potential immunoregulatory functions but only limited insight in their expression on immune regulatory cell subsets, prompting us to investigate Siglec expression on MDSCs. We determined the expression of different Siglec family members on monocytic-MDSCs (M-MDSCs) and polymorphnuclear-MDSCs (PMN-MDSCs) from blood of glioma patients and healthy donors, as well as from patient-derived tumor material. Furthermore, we investigated the presence of sialic acid ligands for these Siglecs on MDSCs and in the glioma tumor microenvironment. Both MDSC subsets express Siglec-3, -5, -7 and -9, with higher levels of Siglec-3, -7 and -9 on M-MDSCs and higher Siglec-5 levels on PMN-MDSCs. Similar Siglec expression profiles were found on MDSCs from healthy donors. Furthermore, the presence of Siglec-5 and -9 was also confirmed on PMN-MDSCs from glioma tissue. Interestingly, freshly isolated glioma cells predominantly expressed sialic acid ligands for Siglec-7 and -9, which was confirmed in situ. In conclusion, our data show a distinct Siglec expression profile for M- and PMN-MDSCs and propose possible sialic acid-Siglec interactions between glioma cells and MDSCs in the tumor microenvironment.

SUBMITTER: Santegoets KCM

PROVIDER: S-EPMC6529385 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Expression profiling of immune inhibitory Siglecs and their ligands in patients with glioma.

Santegoets Kim C M KCM Gielen Paul R PR Büll Christian C Schulte Barbara M BM Kers-Rebel Esther D ED Küsters Benno B Bossman Sandra A J F H SAJFH Ter Laan Mark M Wesseling Pieter P Adema Gosse J GJ

Cancer immunology, immunotherapy : CII 20190405 6

Gliomas appear to be highly immunosuppressive tumors, with a strong myeloid component. This includes MDSCs, which are a heterogeneous, immature myeloid cell population expressing myeloid markers Siglec-3 (CD33) and CD11b and lacking markers of mature myeloid cells including MHC II. Siglec-3 is a member of the sialic acid-binding immunoglobulin-like lectin (Siglec) family and has been suggested to promote MDSC expansion and suppression. Siglecs form a recently defined family of receptors with pot ...[more]

PMID: 30953118

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Project description:Tumor heterogeneity of high-grade glioma (HGG) is recognized by four clinically relevant subtypes based on core gene signatures. However, molecular signaling in glioma stem cells (GSCs) in individual HGG subtypes is poorly characterized. Previously we identified and characterized two mutually exclusive GSC subtypes with distinct activated signaling pathways and biological phenotypes. One GSC subtype presented with a gene signature resembling Proneural (PN) HGG, whereas the other was similar to Mesenchymal (Mes) HGG. Classical HGG-derived GSCs were sub-classified as either one of these two subtypes. Differential mRNA expression analysis of PN and Mes GSCs identified 5,796 differentially expressed genes, revealing a pronounced correlation with the corresponding PN or Mes HGGs. Mes GSCs displayed more aggressive phenotypes in vitro and as intracranial xenografts in mice. Further, Mes GSCs were markedly resistant to radiation compared with PN GSCs. Expression of ALDH1A3 - one of the most up-regulated Mes representative genes and a universal cancer stem cell marker in non-brain cancers - was associated with self-renewal and a multi-potent stem cell population in Mes but not PN samples. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs in vitro. Lastly, radiation treatment of PN GSCs up-regulated Mes-associated markers and down-regulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs in vitro. Taken together, our data suggest that two subtypes of GSCs, harboring distinct metabolic signaling pathways, represent intertumoral glioma heterogeneity and highlight previously unidentified roles of ALDH1A3-associated signaling that promotes aberrant proliferation of Mes HGGs and GSCs. Inhibition of ALDH1A3-mediated pathways therefore might provide a promising therapeutic approach for a subset of HGGs with the Mes signature. Here, we describe the gene expression analysis, including pre-processing methods for the data published by Mao and colleagues in PNAS [1], integration of microarray data from this study with The Cancer Genome Atlas (TCGA) glioblastoma data and also with another published study.

Dataset Information

Expression profiling of immune inhibitory Siglecs and their ligands in patients with glioma.

Publications

Expression profiling of immune inhibitory Siglecs and their ligands in patients with glioma.

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