1p/19q co-deletion status is associated with distinct tumor-associated macrophage infiltration in IDH mutated lower-grade gliomas

• Published in: Cellular oncology (Dordrecht) 2021-02, Vol.44 (1), p.193-204
• Main Authors: Zhang, Yanyu, Xie, Yuan, He, Liqun, Tang, Jiefu, He, Qiyuan, Cao, Qingze, Cui, Langjun, Guo, Wei, Hua, Kai, Dimberg, Anna, Wang, Liang, Zhang, Lei
• Format: Article
• Language: English
• Subjects: 19q; Animals; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Brain Neoplasms - genetics; Brain Neoplasms - pathology; Cancer Research; CD86 antigen; Chromosome Deletion; Chromosomes, Human, Pair 1 - genetics; Chromosomes, Human, Pair 19 - genetics; Colony-stimulating factor; Disease Progression; Female; Gene expression; Genotype & phenotype; Glioma; Glioma - genetics; Glioma - pathology; Humans; Infiltration; Isocitrate dehydrogenase; Isocitrate Dehydrogenase - genetics; LGG; Macrophage colony-stimulating factor; Macrophage Colony-Stimulating Factor - metabolism; Metastases; Mice; Mice, Inbred C57BL; Monocytes - pathology; Mutation - genetics; Neoplasm Grading; Oncology; Original Paper; Pathology; Phenotype; Phenotypes; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Ribonucleic acid; RNA; THP-1 Cells; Transcriptomes; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; Tumor necrosis factor; Tumor-associated macrophage; Tumor-Associated Macrophages - metabolism; Tumor-Associated Macrophages - pathology
• ISSN: 2211-3428; 2211-3436; 2211-3436
• DOI: 10.1007/s13402-020-00561-1

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 IDH-mutated 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. M-CSF 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.