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Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas

Intrinsic malignant brain tumors, such as glioblastomas are frequently resistant to immune checkpoint blockade (ICB) with few hypermutated glioblastomas showing response. Modeling patient-individual resistance is challenging due to the lack of predictive biomarkers and limited accessibility of tissu...

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Main Authors: Aslan, Katrin (Author) , Turco, Verena (Author) , Blobner, Jens (Author) , Sonner, Jana K. (Author) , Liuzzi, Anna Rita (Author) , Núñez, Nicolás Gonzalo (Author) , De Feo, Donatella (Author) , Vollmuth, Philipp (Author) , Fischer, Manuel (Author) , Green, Ed (Author) , Sadik, Ahmed (Author) , Friedrich, Mirco (Author) , Sanghvi, Khwab (Author) , Kilian, Michael (Author) , Cichon, Frederik (Author) , Wolf, Lara (Author) , Jähne, Kristine (Author) , von Landenberg, Anna (Author) , Bunse, Lukas (Author) , Sahm, Felix (Author) , Schrimpf, Daniel (Author) , Meyer, Jochen (Author) , Alexander, Allen (Author) , Brugnara, Gianluca (Author) , Röth, Ralph (Author) , Pfleiderer, Kira (Author) , Niesler, Beate (Author) , Deimling, Andreas von (Author) , Opitz, Christiane (Author) , Breckwoldt, Michael O. (Author) , Heiland, Sabine (Author) , Bendszus, Martin (Author) , Wick, Wolfgang (Author) , Becher, Burkhard (Author) , Platten, Michael (Author)
Format: Article (Journal)
Language:English
Published: 18 February 2020
In: Nature Communications
Year: 2020, Volume: 11
ISSN:2041-1723
DOI:10.1038/s41467-020-14642-0
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41467-020-14642-0
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41467-020-14642-0
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Author Notes:Katrin Aslan, Verena Turco, Jens Blobner, Jana K. Sonner, Anna Rita Liuzzi, Nicolás Gonzalo Núñez, Donatella De Feo, Philipp Kickingereder, Manuel Fischer, Ed Green, Ahmed Sadik, Mirco Friedrich, Khwab Sanghvi, Michael Kilian, Frederik Cichon, Lara Wolf, Kristine Jähne, Anna von Landenberg, Lukas Bunse, Felix Sahm, Daniel Schrimpf, Jochen Meyer, Allen Alexander, Gianluca Brugnara, Ralph Röth, Kira Pfleiderer, Beate Niesler, Andreas von Deimling, Christiane Opitz, Michael O. Breckwoldt, Sabine Heiland, Martin Bendszus, Wolfgang Wick, Burkhard Becher & Michael Platten
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Summary:Intrinsic malignant brain tumors, such as glioblastomas are frequently resistant to immune checkpoint blockade (ICB) with few hypermutated glioblastomas showing response. Modeling patient-individual resistance is challenging due to the lack of predictive biomarkers and limited accessibility of tissue for serial biopsies. Here, we investigate resistance mechanisms to anti-PD-1 and anti-CTLA-4 therapy in syngeneic hypermutated experimental gliomas and show a clear dichotomy and acquired immune heterogeneity in ICB-responder and non-responder tumors. We made use of this dichotomy to establish a radiomic signature predicting tumor regression after pseudoprogression induced by ICB therapy based on serial magnetic resonance imaging. We provide evidence that macrophage-driven ICB resistance is established by CD4 T cell suppression and Treg expansion in the tumor microenvironment via the PD-L1/PD-1/CD80 axis. These findings uncover an unexpected heterogeneity of response to ICB in strictly syngeneic tumors and provide a rationale for targeting PD-L1-expressing tumor-associated macrophages to overcome resistance to ICB.
Item Description:Gesehen am 22.10.2020
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-020-14642-0

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