Tumor-associated reactive astrocytes aid the evolution of immunosuppressive environment in glioblastoma
Henrik Heiland D, Ravi VM, Behringer SP, Frenking JH, Wurm J, Joseph K, Garrelfs NWC, Strähle J, Heynckes S, Grauvogel J, Franco P, Mader I, Schneider M, Potthoff AL, Delev D, Hofmann UG, Fung C, Beck J, Sankowski R, Prinz M, Schnell O.
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 antiinflammatory cytokines towards a pro-inflammatory environment.
