Transcriptional regulatory networks of tumor-associated macrophages that drive malignancy in mesenchymal glioblastoma

Abstract

Background Glioblastoma (GBM) is a complex disease with extensive molecular and transcriptional heterogeneity. GBM can be subcategorized into four distinct subtypes; tumors that shift towards the mesenchymal phenotype upon recurrence are generally associated with treatment resistance, unfavorable prognosis, and the infiltration of pro-tumorigenic macrophages. Results We explore the transcriptional regulatory networks of mesenchymal-associated tumor-associated macrophages (MA-TAMs), which drive the malignant phenotypic state of GBM, and identify macrophage receptor with collagenous structure (MARCO) as the most highly differentially expressed gene. MARCOhigh TAMs induce a phenotypic shift towards mesenchymal cellular state of glioma stem cells, promoting both invasive and proliferative activities, as well as therapeutic resistance to irradiation. MARCOhigh TAMs also significantly accelerate tumor engraftment and growth in vivo. Moreover, both MA-TAM master regulators and their target genes are significantly correlated with poor clinical outcomes and are often associated with genomic aberrations in neurofibromin 1 (NF1) and phosphoinositide 3-kinases/mammalian target of rapamycin/Akt pathway (PI3K-mTOR-AKT)-related genes. We further demonstrate the origination of MA-TAMs from peripheral blood, as well as their potential association with tumor-induced polarization states and immunosuppressive environments. Conclusions Collectively, our study characterizes the global transcriptional profile of TAMs driving mesenchymal GBM pathogenesis, providing potential therapeutic targets for improving the effectiveness of GBM immunotherapy.

PDIA5 is Correlated With Immune Infiltration and Predicts Poor Prognosis in Gliomas

“…Additionally, growing evidence have identified that tumor-associated macrophages (TAMs) played a key role in the progression and metastasis of tumor cells ( 64 – 66 ). As the result of the impact of metabolites of malignant cells, TAMs in the tumor microenvironment make corresponding metabolic changes, leading to functional reprogramming of TAMs which includes the M2 polarization of macrophages, and alterations of cytokines and angiogenic factors secretion.…”

Perspective of mesenchymal transformation in glioblastoma

“…An interesting observation from this study was that CSF-1R blockade did not affect the number of TAMs, but rather, decreased pro-tumorigenic M2 markers in TAMs, suggesting that TAMs are “re-educated” to perform antitumor activity. Furthermore, it was shown that CSF-1R inhibition by PLX3397, which hampers the tyrosine kinase activity of CSF-1R, prevented radiation-recruited monocytes from differentiating into immunosuppressive and pro-tumorigenic M2 macrophages [ 131 , 143 , 170 ]. Of note, GBMs may also develop resistance to sustained CSF-1R blockade.…”

“…Generally, two types of mesenchymal GBM have been described: microenvironment-driven and microenvironment-independent mesenchymal GBM [ 100 , 161 ]. Non-neoplastic cells of microenvironmental components, especially brain-resident microglia and infiltrated monocyte-derived macrophages, have been shown closely associated with the development of mesenchymal GBM [ 11 , 35 , 48 , 130 , 131 ]. Bhat et al reported that the mesenchymal signature is lost in patient-derived glioma sphere cultures and xenograft models despite originating from mesenchymal tumors, suggesting the necessity of human tumor microenvironmental factors in acquiring and maintaining the mesenchymal phenotypic state of GBMs [ 11 ].…”

“…Bhat et al reported that the mesenchymal signature is lost in patient-derived glioma sphere cultures and xenograft models despite originating from mesenchymal tumors, suggesting the necessity of human tumor microenvironmental factors in acquiring and maintaining the mesenchymal phenotypic state of GBMs [ 11 ]. Furthermore, the global and regulatory transcriptional profile of tumor-associated macrophages that drive mesenchymal phenotype in GBM has recently been identified, further highlighting the association between microenvironmental components and mesenchymal GBM [ 131 ]. On the other hand, mesenchymal transformation has also been reported to occur in a glioma cell-intrinsic manner [ 11 , 47 ].…”

Myeloid Cells in Glioblastoma Microenvironment

“…Since differential expression of binding partners influences PU.1 genomic occupation, binding partners that are absent in MG and expressed in BMDMs can sculpt genomic PU.1 occupancy and play a role in brain tumors [ 43 ]. The study of the dynamic regulatory networks of blood-derived TAMs in GBM has indeed recently identified a macrophage receptor with collagenous structure (MARCO) that promotes proliferative activities and therapeutic resistance to irradiation of glioma stem cells as well as tumor engraftment and growth in vivo [ 54 ]. Moreover, therapeutic strategies such as radiotherapy may alter the transcriptional characteristics of TAM subpopulations over time.…”