T-cell dysfunction in the glioblastoma microenvironment is mediated by myeloid cells releasing interleukin-10.
IF: 17.694
Cited by: 71


Despite recent advances in cancer immunotherapy, certain tumor types, such as Glioblastomas, are highly resistant due to their tumor microenvironment disabling the anti-tumor immune response. Here we show, by applying an in-silico multidimensional model integrating spatially resolved and single-cell gene expression data of 45,615 immune cells from 12 tumor samples, that a subset of Interleukin-10-releasing HMOX1+ myeloid cells, spatially localizing to mesenchymal-like tumor regions, drive T-cell exhaustion and thus contribute to the immunosuppressive tumor microenvironment. These findings are validated using a human ex-vivo neocortical glioblastoma model inoculated with patient derived peripheral T-cells to simulate the immune compartment. This model recapitulates the dysfunctional transformation of tumor infiltrating T-cells. Inhibition of the JAK/STAT pathway rescues T-cell functionality both in our model and in-vivo, providing further evidence of IL-10 release being an important driving force of tumor immune escape. Our results thus show that integrative modelling of single cell and spatial transcriptomics data is a valuable tool to interrogate the tumor immune microenvironment and might contribute to the development of successful immunotherapies.


Spatial Transcriptomics

MeSH terms

Brain Neoplasms
Cell Communication
Cell Line, Tumor
Healthy Volunteers
Heme Oxygenase-1
Janus Kinase Inhibitors
Janus Kinases
Middle Aged
Myeloid Cells
Primary Cell Culture
STAT Transcription Factors
Signal Transduction
Single-Cell Analysis
Tissue Culture Techniques
Tumor Escape
Tumor Microenvironment


Ravi, Vidhya M
Neidert, Nicolas
Will, Paulina
Joseph, Kevin
Maier, Julian P
Kückelhaus, Jan
Vollmer, Lea
Goeldner, Jonathan M
Behringer, Simon P
Scherer, Florian
Boerries, Melanie
Follo, Marie
Weiss, Tobias
Delev, Daniel
Kernbach, Julius
Franco, Pamela
Schallner, Nils
Dierks, Christine
Carro, Maria Stella
Hofmann, Ulrich G
Fung, Christian
Sankowski, Roman
Prinz, Marco
Beck, Jürgen
Salié, Henrike
Bengsch, Bertram
Schnell, Oliver
Heiland, Dieter Henrik

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