Ferroptosis-armed dendritic cell vaccines for glioma immunotherapy
Mariia Saviuk 1 2, Victoria D Turubanova 1 3, Sara De Brée 1 2, Sandra Van Lint 2 4, Teresa Mendes Maia 5 6 7, Simon Devos 5 6 7, Iuliia Efimova 1 2, Julie Braet 2 4, Lore Van Oudenhove 8, Gitta Boons 8, Faye Naessens 1 2, Robin Demuynck 1 2, Ellen Saeys 1 2, Christian Vanhove 9, Lukas Bunse 10 11, Peter M van Endert 12 13, Robrecht Raedt 14, Maria V Vedunova 15, Olga Krysko 1, Roosmarijn E Vandenbroucke 16 17, Karim Vermaelen 2 4, Tatiana A Mishchenko 15, Elena Catanzaro # 18 19, Dmitri V Krysko # 1 2
A prophylactic DC vaccine loaded with ferroptotic (iron-dependent cell death) glioma cell line lysates protected against glioma growth in mice, superior to immunogenic cell death (ICD) or freeze/thaw (non-ICD) lysates. The vaccine also mediated therapeutic efficacy, induced antigen-specific CTL responses in SLOs, and increased i.t. CTLs (particularly CD39+ effector-memory cells) compared to controls. Ferroptosis induced ICD markers on glioma cells, and blocking calreticulin or ATP, but not HMGB1, abrogated vaccine efficacy. Ferroptotic lysates activated DCs and displayed a unique proteomic profile, potentially presenting novel TAAs.
Contributed by Alex Najibi
Mariia Saviuk 1 2, Victoria D Turubanova 1 3, Sara De Brée 1 2, Sandra Van Lint 2 4, Teresa Mendes Maia 5 6 7, Simon Devos 5 6 7, Iuliia Efimova 1 2, Julie Braet 2 4, Lore Van Oudenhove 8, Gitta Boons 8, Faye Naessens 1 2, Robin Demuynck 1 2, Ellen Saeys 1 2, Christian Vanhove 9, Lukas Bunse 10 11, Peter M van Endert 12 13, Robrecht Raedt 14, Maria V Vedunova 15, Olga Krysko 1, Roosmarijn E Vandenbroucke 16 17, Karim Vermaelen 2 4, Tatiana A Mishchenko 15, Elena Catanzaro # 18 19, Dmitri V Krysko # 1 2
A prophylactic DC vaccine loaded with ferroptotic (iron-dependent cell death) glioma cell line lysates protected against glioma growth in mice, superior to immunogenic cell death (ICD) or freeze/thaw (non-ICD) lysates. The vaccine also mediated therapeutic efficacy, induced antigen-specific CTL responses in SLOs, and increased i.t. CTLs (particularly CD39+ effector-memory cells) compared to controls. Ferroptosis induced ICD markers on glioma cells, and blocking calreticulin or ATP, but not HMGB1, abrogated vaccine efficacy. Ferroptotic lysates activated DCs and displayed a unique proteomic profile, potentially presenting novel TAAs.
Contributed by Alex Najibi
ABSTRACT: The type of cell death has proven to play a crucial role in cancer immunotherapy efficacy. Immunogenic cell death (ICD) enhances tumor adjuvanticity and antigenicity by releasing danger signals and altering the immune peptidome. The immunogenicity of ferroptosis, an iron-dependent form of cell death, remains uncertain. Here, we show that dendritic cell (DC) vaccines loaded with ferroptotic lysates protect mice against glioma growth, inducing IFN-_ production, and promoting robust CD8_ T cell infiltration, activation, and effector memory formation in the tumor microenvironment. The intrinsic immunogenicity of ferroptosis was independent of the glioma type and the ferroptosis inducer. Instead, it critically required the presence of the damage-associated molecular patterns calreticulin and ATP, rather than involving HMGB1-TLR4 signaling. However, supplementing these DAMPs into DC vaccines loaded with non-ICD lysates did not restore efficacy to the level of the ferroptosis-based DC vaccine, suggesting a more complex mechanism beyond a purely DAMP-mediated effect. These findings demonstrate that ferroptosis-loaded DC vaccines elicit a potent, tumor-specific immune response, capable of eradicating intracranial gliomas in mice, which highlights their potential in cancer immunotherapy.
Author Info:
1Cell Death Investigation and Therapy (CDIT) Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent Unive
rsity, Ghent, Belgium.
2Cancer Research Institute Ghent, Ghent, Belgium.
3Institute of Neurosciences, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny, Russia.
4Thoracic Tumor Immunology Laboratory (TTIL), Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Science, Ghent University, Ghent, Belgium.
5VIB Proteomics Core, VIB, Ghent, Belgium.
6VIB-UGent Center for Medical Biotechnology, VIB, Ghent, Belgium.
7Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
8myNEO Therapeutics, Ghent, Belgium.
9IBiTech-MEDISIP-Infinity Laboratory, Department of Electronics and Information Systems, Faculty of Engineering and Architecture, Ghent University, Ghent, Belgium.
10Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
11Neurology Clinic, Medical Faculty Mannheim, University Heidelberg, Mannheim, Germany.
12Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, Paris, France.
13Service Immunologie Biologique, AP-HP, Hôpital Universitaire Necker-Enfants Malades, Paris, France.
144Brain, Department of Head and Skin, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
15Institute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny, Russia.
16VIB Center for Inflammation Research, Ghent, Belgium.
17Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium.
18Cell Death Investigation and Therapy (CDIT) Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. elena.catanzaro@ugent.be.
19Cancer Research Institute Ghent, Ghent, Belgium. elena.catanzaro@ugent.be.
#Contributed equally.
