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Sci Transl Med. 2016 Mar 2;8(328):328ra27. doi: 10.1126/scitranslmed.aae0105.

Dendritic cell vaccines based on immunogenic cell death elicit danger signals and T cell-driven rejection of high-grade glioma.

Author information

1
Cell Death Research and Therapy Laboratory, Department of Cellular and Molecular Medicine, Katholieke Universiteit (KU) Leuven, Leuven 3000, Belgium.
2
Laboratory of Pediatric Immunology, Department of Microbiology and Immunology, KU Leuven, Leuven 3000, Belgium.
3
Department of Neurosciences, Research Group-Neuroanatomy and Neurosurgery, KU Leuven, Leuven 3000, Belgium.
4
EPIRUS Biopharmaceuticals Netherlands BV, 3584 Utrecht, Netherlands.
5
Laboratory of Pediatric Immunology, Department of Microbiology and Immunology, KU Leuven, Leuven 3000, Belgium. patrizia.agostinis@med.kuleuven.be vangoolstefaan@gmail.com.
6
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.

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.

PMID:
26936504
DOI:
10.1126/scitranslmed.aae0105
[Indexed for MEDLINE]

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