Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas
Standard
Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas. / Aslan, Katrin; Turco, Verena; Blobner, Jens; Sonner, Jana K; Liuzzi, Anna Rita; Núñez, Nicolás Gonzalo; De Feo, Donatella; Kickingereder, Philipp; Fischer, Manuel; Green, Ed; Sadik, Ahmed; Friedrich, Mirco; Sanghvi, Khwab; Kilian, Michael; Cichon, Frederik; Wolf, Lara; Jähne, Kristine; von Landenberg, Anna; Bunse, Lukas; Sahm, Felix; Schrimpf, Daniel; Meyer, Jochen; Alexander, Allen; Brugnara, Gianluca; Röth, Ralph; Pfleiderer, Kira; Niesler, Beate; von Deimling, Andreas; Opitz, Christiane; Breckwoldt, Michael O; Heiland, Sabine; Bendszus, Martin; Wick, Wolfgang; Becher, Burkhard; Platten, Michael.
in: NAT COMMUN, Jahrgang 11, Nr. 1, 18.02.2020, S. 931.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas
AU - Aslan, Katrin
AU - Turco, Verena
AU - Blobner, Jens
AU - Sonner, Jana K
AU - Liuzzi, Anna Rita
AU - Núñez, Nicolás Gonzalo
AU - De Feo, Donatella
AU - Kickingereder, Philipp
AU - Fischer, Manuel
AU - Green, Ed
AU - Sadik, Ahmed
AU - Friedrich, Mirco
AU - Sanghvi, Khwab
AU - Kilian, Michael
AU - Cichon, Frederik
AU - Wolf, Lara
AU - Jähne, Kristine
AU - von Landenberg, Anna
AU - Bunse, Lukas
AU - Sahm, Felix
AU - Schrimpf, Daniel
AU - Meyer, Jochen
AU - Alexander, Allen
AU - Brugnara, Gianluca
AU - Röth, Ralph
AU - Pfleiderer, Kira
AU - Niesler, Beate
AU - von Deimling, Andreas
AU - Opitz, Christiane
AU - Breckwoldt, Michael O
AU - Heiland, Sabine
AU - Bendszus, Martin
AU - Wick, Wolfgang
AU - Becher, Burkhard
AU - Platten, Michael
PY - 2020/2/18
Y1 - 2020/2/18
N2 - 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.
AB - 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.
KW - Animals
KW - Antineoplastic Agents, Immunological/pharmacology
KW - B7-1 Antigen/immunology
KW - B7-H1 Antigen/immunology
KW - Brain Neoplasms/diagnostic imaging
KW - CD8-Positive T-Lymphocytes/drug effects
KW - CTLA-4 Antigen/antagonists & inhibitors
KW - Cell Line, Tumor/transplantation
KW - Disease Models, Animal
KW - Drug Resistance, Neoplasm/genetics
KW - Female
KW - Glioma/diagnostic imaging
KW - Humans
KW - Macrophages/drug effects
KW - Magnetic Resonance Imaging
KW - Male
KW - Programmed Cell Death 1 Receptor/antagonists & inhibitors
KW - Signal Transduction/drug effects
KW - T-Lymphocytes, Regulatory/drug effects
KW - Tumor Microenvironment/drug effects
U2 - 10.1038/s41467-020-14642-0
DO - 10.1038/s41467-020-14642-0
M3 - SCORING: Journal article
C2 - 32071302
VL - 11
SP - 931
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -