Abstract
Reactive astrocytes evolve after brain injury, inflammatory and degenerative diseases, whereby they undergo transcriptomic re-programming. In malignant brain tumors, their function and crosstalk to other components of the environment is poorly understood. Here we report a distinct transcriptional phenotype of reactive astrocytes from glioblastoma linked to JAK/STAT pathway activation. Subsequently, we investigate the origin of astrocytic transformation by a microglia loss-of-function model in a human organotypic slice model with injected tumor cells. RNA-seq based gene expression analysis of astrocytes reveals a distinct astrocytic phenotype caused by the coexistence of microglia and astrocytes in the tumor environment, which leads to a large release of anti-inflammatory cytokines such as TGFβ, IL10 and G-CSF. Inhibition of the JAK/STAT pathway shifts the balance of pro- and anti-inflammatory cytokines towards a pro-inflammatory environment. The complex interaction of astrocytes and microglia cells promotes an immunosuppressive environment, suggesting that tumor-associated astrocytes contribute to anti-inflammatory responses.
Highlights
Reactive astrocytes evolve after brain injury, inflammatory and degenerative diseases, whereby they undergo transcriptomic re-programming
Our results indicate that a distinct reactive astrocytic subtype is mediated by a joint alteration of the surrounding secretome caused by both the tumor and microglia and that only in their presence, high concentrations of anti-inflammatory IL10 and TGFβ are detectable in the tumor microenvironment, which contributes substantially to the properties of an immunological “cold”-tumor environment
In the reactive astrocytes from the tumor we identified an increased expression of immune associated genes such as CHI3L1, HLA-DRA, CD274, HLA-DRB3, CD37 (Fig. 1b), as well as genes that contributed to proliferation (MKI67, ANXA2) and complement components (C1S, C1R) (Fig. 1b and Supplementary Fig. 2)
Summary
Reactive astrocytes evolve after brain injury, inflammatory and degenerative diseases, whereby they undergo transcriptomic re-programming. We report a distinct transcriptional phenotype of reactive astrocytes from glioblastoma linked to JAK/STAT pathway activation. The complex interaction of astrocytes and microglia cells promotes an immunosuppressive environment, suggesting that tumor-associated astrocytes contribute to anti-inflammatory responses. We showed that these tumor-associated astrocytes were marked by JAK/STAT pathway activation and CD274 expression, which were confirmed in a set of de-novo and recurrent glioblastoma specimens. Our results indicate that a distinct reactive astrocytic subtype is mediated by a joint alteration of the surrounding secretome caused by both the tumor and microglia and that only in their presence, high concentrations of anti-inflammatory IL10 and TGFβ are detectable in the tumor microenvironment, which contributes substantially to the properties of an immunological “cold”-tumor environment
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