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

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. [ABSTRACT FROM AUTHOR]