T-cell dysfunction in the glioblastoma microenvironment is mediated by myeloid cells releasing interleukin-10

Vidhya M. Ravi, Nicolas Neidert, Paulina Will, Kevin Joseph, Julian P. Maier, Jan Kückelhaus, Lea Vollmer, Jonathan M. Goeldner, Simon P. Behringer, Florian Scherer, Melanie Boerries, Marie Follo, Tobias Weiss, Daniel Delev, Julius Kernbach, Pamela Franco, Nils Schallner, Christine Dierks, Maria Stella Carro, Ulrich G. Hofmann, Christian Fung, Roman Sankowski, Marco Prinz, Jürgen Beck, Henrike Salié, Bertram Bengsch, Oliver Schnell and Dieter Henrik Heiland ()
Additional contact information
Vidhya M. Ravi: Medical Center-University of Freiburg
Nicolas Neidert: Medical Center-University of Freiburg
Paulina Will: Medical Center-University of Freiburg
Kevin Joseph: Medical Center-University of Freiburg
Julian P. Maier: Medical Center-University of Freiburg
Jan Kückelhaus: Medical Center-University of Freiburg
Lea Vollmer: Medical Center-University of Freiburg
Jonathan M. Goeldner: Medical Center-University of Freiburg
Simon P. Behringer: Medical Center-University of Freiburg
Florian Scherer: University of Freiburg
Melanie Boerries: University of Freiburg
Marie Follo: University of Freiburg
Tobias Weiss: University Hospital Zurich and University of Zurich
Daniel Delev: RWTH University of Aachen
Julius Kernbach: RWTH University of Aachen
Pamela Franco: Medical Center-University of Freiburg
Nils Schallner: University of Freiburg
Christine Dierks: University of Freiburg
Maria Stella Carro: Medical Center-University of Freiburg
Ulrich G. Hofmann: Medical Center-University of Freiburg
Christian Fung: Medical Center-University of Freiburg
Roman Sankowski: University of Freiburg
Marco Prinz: University of Freiburg
Jürgen Beck: Medical Center-University of Freiburg
Henrike Salié: University of Freiburg
Bertram Bengsch: University of Freiburg
Oliver Schnell: Medical Center-University of Freiburg
Dieter Henrik Heiland: Medical Center-University of Freiburg

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28523-1

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DOI: 10.1038/s41467-022-28523-1

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