Tumor-associated reactive astrocytes aid the evolution of immunosuppressive environment in glioblastoma

Dieter Henrik Heiland (), Vidhya M. Ravi, Simon P. Behringer, Jan Hendrik Frenking, Julian Wurm, Kevin Joseph, Nicklas W. C. Garrelfs, Jakob Strähle, Sabrina Heynckes, Jürgen Grauvogel, Pamela Franco, Irina Mader, Matthias Schneider, Anna-Laura Potthoff, Daniel Delev, Ulrich G. Hofmann, Christian Fung, Jürgen Beck, Roman Sankowski, Marco Prinz and Oliver Schnell
Additional contact information
Dieter Henrik Heiland: University of Freiburg
Vidhya M. Ravi: University of Freiburg
Simon P. Behringer: University of Freiburg
Jan Hendrik Frenking: University of Freiburg
Julian Wurm: University of Freiburg
Kevin Joseph: University of Freiburg
Nicklas W. C. Garrelfs: University of Freiburg
Jakob Strähle: University of Freiburg
Sabrina Heynckes: University of Freiburg
Jürgen Grauvogel: University of Freiburg
Pamela Franco: University of Freiburg
Irina Mader: University of Freiburg
Matthias Schneider: University of Bonn
Anna-Laura Potthoff: University of Bonn
Daniel Delev: University of Aachen
Ulrich G. Hofmann: University of Freiburg
Christian Fung: University of Freiburg
Jürgen Beck: University of Freiburg
Roman Sankowski: Freiburg University
Marco Prinz: Freiburg University
Oliver Schnell: University of Freiburg

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10493-6

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