Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas

Katrin Aslan, Verena Turco, Jens Blobner, Jana K. Sonner, Anna Rita Liuzzi, Nicolás Gonzalo Núñez, Donatella Feo, Philipp Kickingereder, Manuel Fischer, Ed Green, Ahmed Sadik, Mirco Friedrich, Khwab Sanghvi, Michael Kilian, Frederik Cichon, Lara Wolf, Kristine Jähne, Anna Landenberg, Lukas Bunse, Felix Sahm, Daniel Schrimpf, Jochen Meyer, Allen Alexander, Gianluca Brugnara, Ralph Röth, Kira Pfleiderer, Beate Niesler, Andreas Deimling, Christiane Opitz, Michael O. Breckwoldt, Sabine Heiland, Martin Bendszus, Wolfgang Wick, Burkhard Becher and Michael Platten ()
Additional contact information
Katrin Aslan: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)
Verena Turco: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)
Jens Blobner: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)
Jana K. Sonner: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)
Anna Rita Liuzzi: University of Zurich
Nicolás Gonzalo Núñez: University of Zurich
Donatella Feo: University of Zurich
Philipp Kickingereder: Heidelberg University Medical Center
Manuel Fischer: Heidelberg University Medical Center
Ed Green: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)
Ahmed Sadik: Brain Cancer Metabolism Group, German Cancer Research Center (DKFZ)
Mirco Friedrich: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)
Khwab Sanghvi: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)
Michael Kilian: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)
Frederik Cichon: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)
Lara Wolf: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)
Kristine Jähne: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)
Anna Landenberg: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)
Lukas Bunse: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)
Felix Sahm: DKTK Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ)
Daniel Schrimpf: DKTK Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ)
Jochen Meyer: DKTK Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ)
Allen Alexander: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)
Gianluca Brugnara: Heidelberg University Medical Center
Ralph Röth: University of Heidelberg
Kira Pfleiderer: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)
Beate Niesler: University of Heidelberg
Andreas Deimling: DKTK Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ)
Christiane Opitz: Brain Cancer Metabolism Group, German Cancer Research Center (DKFZ)
Michael O. Breckwoldt: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)
Sabine Heiland: Heidelberg University Medical Center
Martin Bendszus: Heidelberg University Medical Center
Wolfgang Wick: Heidelberg University Medical Center
Burkhard Becher: University of Zurich
Michael Platten: DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ)

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-14642-0

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