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T-cell dysfunction in the glioblastoma microenvironment is mediated by myeloid cells releasing interleukin-10.
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.
Afiliación
  • Ravi VM; Microenvironment and Immunology Research Laboratory, Medical Center-University of Freiburg, Freiburg, Germany.
  • Neidert N; Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany.
  • Will P; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Joseph K; Neuroelectronic Systems, Medical Center-University of Freiburg, Freiburg, Germany.
  • Maier JP; Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Freiburg, Germany.
  • Kückelhaus J; Microenvironment and Immunology Research Laboratory, Medical Center-University of Freiburg, Freiburg, Germany.
  • Vollmer L; Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany.
  • Goeldner JM; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Behringer SP; Translational NeuroOncology Research Group, Medical Center-University of Freiburg, Freiburg, Germany.
  • Scherer F; Microenvironment and Immunology Research Laboratory, Medical Center-University of Freiburg, Freiburg, Germany.
  • Boerries M; Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany.
  • Follo M; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Weiss T; Microenvironment and Immunology Research Laboratory, Medical Center-University of Freiburg, Freiburg, Germany.
  • Delev D; Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany.
  • Kernbach J; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Franco P; Microenvironment and Immunology Research Laboratory, Medical Center-University of Freiburg, Freiburg, Germany.
  • Schallner N; Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany.
  • Dierks C; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Carro MS; Microenvironment and Immunology Research Laboratory, Medical Center-University of Freiburg, Freiburg, Germany.
  • Hofmann UG; Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany.
  • Fung C; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Sankowski R; Microenvironment and Immunology Research Laboratory, Medical Center-University of Freiburg, Freiburg, Germany.
  • Prinz M; Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany.
  • Beck J; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Salié H; Microenvironment and Immunology Research Laboratory, Medical Center-University of Freiburg, Freiburg, Germany.
  • Bengsch B; Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany.
  • Schnell O; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Heiland DH; Microenvironment and Immunology Research Laboratory, Medical Center-University of Freiburg, Freiburg, Germany.
Nat Commun ; 13(1): 925, 2022 02 17.
Article en En | MEDLINE | ID: mdl-35177622
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Linfocitos T / Interleucina-10 / Glioblastoma / Células Mieloides Tipo de estudio: Observational_studies / Prognostic_studies Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2022 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Linfocitos T / Interleucina-10 / Glioblastoma / Células Mieloides Tipo de estudio: Observational_studies / Prognostic_studies Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2022 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido