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Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas

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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, Vol. 11, No. 1, 18.02.2020, p. 931.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Aslan, K, Turco, V, Blobner, J, Sonner, JK, Liuzzi, AR, Núñez, NG, De Feo, D, Kickingereder, P, Fischer, M, Green, E, Sadik, A, Friedrich, M, Sanghvi, K, Kilian, M, Cichon, F, Wolf, L, Jähne, K, von Landenberg, A, Bunse, L, Sahm, F, Schrimpf, D, Meyer, J, Alexander, A, Brugnara, G, Röth, R, Pfleiderer, K, Niesler, B, von Deimling, A, Opitz, C, Breckwoldt, MO, Heiland, S, Bendszus, M, Wick, W, Becher, B & Platten, M 2020, 'Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas', NAT COMMUN, vol. 11, no. 1, pp. 931. https://doi.org/10.1038/s41467-020-14642-0

APA

Aslan, K., Turco, V., Blobner, J., Sonner, J. K., Liuzzi, A. R., Núñez, N. G., De Feo, D., Kickingereder, P., Fischer, M., Green, E., Sadik, A., Friedrich, M., Sanghvi, K., Kilian, M., Cichon, F., Wolf, L., Jähne, K., von Landenberg, A., Bunse, L., ... Platten, M. (2020). Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas. NAT COMMUN, 11(1), 931. https://doi.org/10.1038/s41467-020-14642-0

Vancouver

Aslan K, Turco V, Blobner J, Sonner JK, Liuzzi AR, Núñez NG et al. Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas. NAT COMMUN. 2020 Feb 18;11(1):931. https://doi.org/10.1038/s41467-020-14642-0

Bibtex

@article{31e4b85405a74904a4b00b3700bef1b5,
title = "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.",
keywords = "Animals, Antineoplastic Agents, Immunological/pharmacology, B7-1 Antigen/immunology, B7-H1 Antigen/immunology, Brain Neoplasms/diagnostic imaging, CD8-Positive T-Lymphocytes/drug effects, CTLA-4 Antigen/antagonists & inhibitors, Cell Line, Tumor/transplantation, Disease Models, Animal, Drug Resistance, Neoplasm/genetics, Female, Glioma/diagnostic imaging, Humans, Macrophages/drug effects, Magnetic Resonance Imaging, Male, Programmed Cell Death 1 Receptor/antagonists & inhibitors, Signal Transduction/drug effects, T-Lymphocytes, Regulatory/drug effects, Tumor Microenvironment/drug effects",
author = "Katrin Aslan and Verena Turco and Jens Blobner and Sonner, {Jana K} and Liuzzi, {Anna Rita} and N{\'u}{\~n}ez, {Nicol{\'a}s Gonzalo} and {De Feo}, Donatella and Philipp Kickingereder and Manuel Fischer and Ed Green and Ahmed Sadik and Mirco Friedrich and Khwab Sanghvi and Michael Kilian and Frederik Cichon and Lara Wolf and Kristine J{\"a}hne and {von Landenberg}, Anna and Lukas Bunse and Felix Sahm and Daniel Schrimpf and Jochen Meyer and Allen Alexander and Gianluca Brugnara and Ralph R{\"o}th and Kira Pfleiderer and Beate Niesler and {von Deimling}, Andreas and Christiane Opitz and Breckwoldt, {Michael O} and Sabine Heiland and Martin Bendszus and Wolfgang Wick and Burkhard Becher and Michael Platten",
year = "2020",
month = feb,
day = "18",
doi = "10.1038/s41467-020-14642-0",
language = "English",
volume = "11",
pages = "931",
journal = "NAT COMMUN",
issn = "2041-1723",
publisher = "NATURE PUBLISHING GROUP",
number = "1",

}

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 -