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 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

doi:10.1038/s41467-020-14642-0

Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas

Nat Commun. 2020 Feb 18;11(1):931. doi: 10.1038/s41467-020-14642-0.

Authors

Katrin Aslan^{1

2

3

4}, Verena Turco^{1

2}, Jens Blobner^{1

2}, Jana K Sonner^{1

2

5}, Anna Rita Liuzzi^#⁶, Nicolás Gonzalo Núñez^#⁶, Donatella De Feo^#⁶, Philipp Kickingereder⁷, Manuel Fischer⁷, Ed Green^{1

2}, Ahmed Sadik⁸, Mirco Friedrich^{1

2}, Khwab Sanghvi^{1

2

3}, Michael Kilian^{1

2

3}, Frederik Cichon^{1

2

3}, Lara Wolf^{1

2}, Kristine Jähne^{1

2}, Anna von Landenberg^{1

2}, Lukas Bunse^{1

2}, Felix Sahm^{9

10}, Daniel Schrimpf^{9

10}, Jochen Meyer^{9

10}, Allen Alexander^{1

3

7}, Gianluca Brugnara⁷, Ralph Röth¹¹, Kira Pfleiderer^{1

7}, Beate Niesler¹¹, Andreas von Deimling^{9

10}, Christiane Opitz⁸, Michael O Breckwoldt^{1

7}, Sabine Heiland⁷, Martin Bendszus⁷, Wolfgang Wick^{12

13

14}, Burkhard Becher⁶, Michael Platten^{15

16

17}

Affiliations

¹ DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
² Department of Neurology, Medical Faculty Mannheim, MCTN, Heidelberg University, Heidelberg, Germany.
³ Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
⁴ Immatics Biotechnologies GmbH, Tübingen, Germany.
⁵ Institute of Neuroimmunology and Multiple Sclerosis, Center for Molecular Neurobiology Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁶ Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
⁷ Department of Neuroradiology, Heidelberg University Medical Center, Heidelberg, Germany.
⁸ Brain Cancer Metabolism Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁹ DKTK Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁰ Department of Neuropathology, Heidelberg University Medical Center, Heidelberg, Germany.
¹¹ nCounter Core Facility, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
¹² Department of Neurology, Heidelberg University Medical Center, Heidelberg, Germany.
¹³ National Center for Tumor Diseases Heidelberg, DKTK, Heidelberg, Germany.
¹⁴ DKTK CCU Neurooncology, DKFZ, Heidelberg, Germany.
¹⁵ DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. [email protected].
¹⁶ Department of Neurology, Medical Faculty Mannheim, MCTN, Heidelberg University, Heidelberg, Germany. [email protected].
¹⁷ Helmholtz Institute for Tranlational Oncology (HI-TRON), Mainz, Germany. [email protected].

^# Contributed equally.

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 T_reg 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents, Immunological / pharmacology*
Antineoplastic Agents, Immunological / therapeutic use
B7-1 Antigen / immunology
B7-1 Antigen / metabolism
B7-H1 Antigen / immunology
B7-H1 Antigen / metabolism
Brain Neoplasms / diagnostic imaging
Brain Neoplasms / drug therapy*
Brain Neoplasms / genetics
Brain Neoplasms / immunology
CD8-Positive T-Lymphocytes / drug effects
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / metabolism
CTLA-4 Antigen / antagonists & inhibitors
CTLA-4 Antigen / immunology
CTLA-4 Antigen / metabolism
Cell Line, Tumor / transplantation
Disease Models, Animal
Drug Resistance, Neoplasm / genetics*
Drug Resistance, Neoplasm / immunology
Female
Glioma / diagnostic imaging
Glioma / drug therapy*
Glioma / genetics
Glioma / immunology
Humans
Macrophages / drug effects
Macrophages / immunology
Macrophages / metabolism
Magnetic Resonance Imaging
Male
Programmed Cell Death 1 Receptor / antagonists & inhibitors
Programmed Cell Death 1 Receptor / immunology
Programmed Cell Death 1 Receptor / metabolism
Signal Transduction / drug effects
Signal Transduction / genetics
Signal Transduction / immunology
T-Lymphocytes, Regulatory / drug effects
T-Lymphocytes, Regulatory / immunology
Tumor Microenvironment / drug effects*
Tumor Microenvironment / genetics
Tumor Microenvironment / immunology

Substances

Antineoplastic Agents, Immunological
B7-1 Antigen
B7-H1 Antigen
CTLA-4 Antigen
Cd274 protein, mouse
Ctla4 protein, mouse
Pdcd1 protein, mouse
Programmed Cell Death 1 Receptor