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

Ravi VM, Neidert N, Will P, Joseph K, Maier JP, Kückelhaus J, Vollmer L, Goeldner JM, Behringer SP, Scherer F, Boerries M, Follo M, Weiss T, Delev D, Kernbach J, Franco P, Schallner N, Dierks C, Carro MS, Hofmann UG, Fung C, Sankowski R, Prinz M, Beck J, Salié H, Bengsch B, Schnell O, Heiland DH (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 13

Article Number: 925

Journal Issue: 1

DOI: 10.1038/s41467-022-28523-1

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.

Authors with CRIS profile

Oliver Schnell

Involved external institutions

Universitätsklinikum Freiburg DE Germany (DE) Albert-Ludwigs-Universität Freiburg DE Germany (DE) Universitätsspital Zürich (USZ) CH Switzerland (CH) Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen DE Germany (DE)

How to cite

APA:

Ravi, V.M., Neidert, N., Will, P., Joseph, K., Maier, J.P., Kückelhaus, J.,... Heiland, D.H. (2022). T-cell dysfunction in the glioblastoma microenvironment is mediated by myeloid cells releasing interleukin-10. Nature Communications, 13(1). https://doi.org/10.1038/s41467-022-28523-1

MLA:

Ravi, Vidhya M., et al. "T-cell dysfunction in the glioblastoma microenvironment is mediated by myeloid cells releasing interleukin-10." Nature Communications 13.1 (2022).

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