1p/19q co-deletion status is associated with distinct tumor-associated macrophage infiltration in IDH mutated lower-grad
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ORIGINAL PAPER
1p/19q co-deletion status is associated with distinct tumor-associated macrophage infiltration in IDH mutated lower-grade gliomas Yanyu Zhang 1,2 & Yuan Xie 1 & Liqun He 3,4 & Jiefu Tang 5 & Qiyuan He 1 & Qingze Cao 1 & Langjun Cui 1 & Wei Guo 6 & Kai Hua 7 & Anna Dimberg 4 & Liang Wang 6 & Lei Zhang 1,5 Accepted: 4 September 2020 # International Society for Cellular Oncology 2020
Abstract Background Tumor-associated macrophages (TAM)s are critical regulators of glioma progression. As yet, however, TAMs in isocitrate dehydrogenase (IDH) mutated lower-grade gliomas (LGGs) have not been thoroughly investigated. The aim of this study was to determine whether 1p/19q co-deletion status affects the TAM phenotype or its prevalence in IDH mutated LGGs. Methods TAMs in IDH mutated LGGs were analyzed using transcriptome data from 230 samples in the TCGA database in combination with transcriptome data from single-cell RNA sequencing of IDH-mutated LGGs. Proteins potentially involved in TAM regulation were examined by immuno-staining in primary LGG samples harboring IDH mutations. Essential signaling pathways regulating TAM phenotypes were investigated in a glioma mouse model using small molecule inhibitors. Results Most of the TAMs in IDH-mutated LGGs expressed the M1 activation markers CD86 and TNF, whereas a subset of individual TAMs co-expressed both M1 and M2-related markers. Bioinformatics analysis in combination with immuno-staining of IDH-mutated patient samples revealed higher amounts of TAMs expressing M2-related markers in 1p/19q non-codeletion IDHmutated LGGs compared to 1p/19q codeletion LGGs. The levels of transforming growth factor beta 1 (TGFβ1) and macrophage colony-stimulating factor (M-CSF) were significantly higher in 1p/19q non-codeletion LGGs than in 1p/19q codeletion LGGs. MCSF and TGFβ1 signal inhibition decreased tumor growth and modulated the TAM phenotype in a glioma mouse model. Conclusions Our data indicate that 1p/19q co-deletion status relates to distinct TAM infiltration in gliomas, which is likely mediated by M-CSF and TGFβ1 signaling. M-CSF and TGFβ1 signaling may play a pivotal role in regulating the TAM phenotype in glioma. Yanyu Zhang, Yuan Xie and Liqun He contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13402-020-00561-1) contains supplementary material, which is available to authorized users. * Liang Wang [email protected]
3
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neuro-injury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin 300052, China
4
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbeck Laboratory, 75185 Uppsala, Sweden
5
Department of Spine Surgery, Huaihua No.2 Hospital, Hunan University of Medicine, Huaihua 418000, China
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Department of Neurosurgery, Tangdu Hospital, Air Force Me
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