title: Dendritic cell vaccines based on immunogenic cell death elicit danger signals and T cell-driven rejection of high-grade glioma.
abstract: The promise of dendritic cell (DC)-based immunotherapy has been established by two decades of translational research. Of the four malignancies most targeted with clinical DC immunotherapy, high-grade glioma (HGG) has shown the highest susceptibility. HGG-induced immunosuppression is a roadblock to immunotherapy, but may be overcome by the application of T helper 1 (T(H)1) immunity-biased, next-generation, DC immunotherapy. To this end, we combined DC immunotherapy with immunogenic cell death (ICD; a modality shown to induce T(H)1 immunity) induced by hypericin-based photodynamic therapy. In an orthotopic HGG mouse model involving prophylactic/curative setups, both biologically and clinically relevant versions of ICD-based DC vaccines provided strong anti-HGG survival benefit. We found that the ability of DC vaccines to elicit HGG rejection was significantly blunted if cancer cell-associated reactive oxygen species and emanating danger signals were blocked either singly or concomitantly, showing hierarchical effect on immunogenicity, or if DCs, DC-associated MyD88 signal, or the adaptive immune system (especially CD8(+) T cells) were depleted. In a curative setting, ICD-based DC vaccines synergized with standard-of-care chemotherapy (temozolomide) to increase survival of HGG-bearing mice by ~300%, resulting in ~50% long-term survivors. Additionally, DC vaccines also induced an immunostimulatory shift in the brain immune contexture from regulatory T cells to T(H)1/cytotoxic T lymphocyte/T(H)17 cells. Analysis of the The Cancer Genome Atlas glioblastoma cohort confirmed that increased intratumor prevalence of T(H)1/cytotoxic T lymphocyte/T(H)17 cells linked genetic signatures was associated with good patient prognosis. Therefore, pending final preclinical checks, ICD-based vaccines can be clinically translated for glioma treatment.
authors.affiliation: Cell Death Research and Therapy Laboratory, Department of Cellular and Molecular Medicine, Katholieke Universiteit (KU) Leuven, Leuven 3000, Belgium.
authors.forename: Abhishek D
authors.initials: AD
authors.lastname: Garg
authors.affiliation: Laboratory of Pediatric Immunology, Department of Microbiology and Immunology, KU Leuven, Leuven 3000, Belgium.
authors.forename: Lien
authors.initials: L
authors.lastname: Vandenberk
authors.affiliation: Laboratory of Pediatric Immunology, Department of Microbiology and Immunology, KU Leuven, Leuven 3000, Belgium.
authors.forename: Carolien
authors.initials: C
authors.lastname: Koks
authors.affiliation: Department of Neurosciences, Research Group-Neuroanatomy and Neurosurgery, KU Leuven, Leuven 3000, Belgium.
authors.forename: Tina
authors.initials: T
authors.lastname: Verschuere
authors.affiliation: EPIRUS Biopharmaceuticals Netherlands BV, 3584 Utrecht, Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.affiliation: Laboratory of Pediatric Immunology, Department of Microbiology and Immunology, KU Leuven, Leuven 3000, Belgium. patrizia.agostinis@med.kuleuven.be vangoolstefaan@gmail.com.
authors.forename: Stefaan W
authors.initials: SW
authors.lastname: Van Gool
authors.affiliation: Cell Death Research and Therapy Laboratory, Department of Cellular and Molecular Medicine, Katholieke Universiteit (KU) Leuven, Leuven 3000, Belgium. patrizia.agostinis@med.kuleuven.be vangoolstefaan@gmail.com.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Agostinis
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects; D000818:Animals; D000873:Anthracenes; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D016923:Cell Death / Q000187:drug effects; D003713:Dendritic Cells / Q000276:immunology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005910:Glioma / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D060787:Neoplasm Grading; D010569:Perylene / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D010778:Photochemotherapy; D017382:Reactive Oxygen Species / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*
chemical_list: D000873:Anthracenes; D019496:Cancer Vaccines; D017382:Reactive Oxygen Species; D010569:Perylene; C004965:hypericin