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Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas.


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.

SUBMITTER: Aslan K 

PROVIDER: S-EPMC7028933 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas.

Aslan Katrin K   Turco Verena V   Blobner Jens J   Sonner Jana K JK   Liuzzi Anna Rita AR   Núñez Nicolás Gonzalo NG   De Feo Donatella D   Kickingereder Philipp P   Fischer Manuel M   Green Ed E   Sadik Ahmed A   Friedrich Mirco M   Sanghvi Khwab K   Kilian Michael M   Cichon Frederik F   Wolf Lara L   Jähne Kristine K   von Landenberg Anna A   Bunse Lukas L   Sahm Felix F   Schrimpf Daniel D   Meyer Jochen J   Alexander Allen A   Brugnara Gianluca G   Röth Ralph R   Pfleiderer Kira K   Niesler Beate B   von Deimling Andreas A   Opitz Christiane C   Breckwoldt Michael O MO   Heiland Sabine S   Bendszus Martin M   Wick Wolfgang W   Becher Burkhard B   Platten Michael M  

Nature communications 20200218 1


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 het  ...[more]

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