title: Targeting of heme oxygenase-1 as a novel immune regulator of neuroblastoma.
abstract: Heme oxygenase (HO)-1 catalyzes the degradation of cytotoxic heme into biliverdin and blocks antitumor immune responses, thus protecting cancer against host defense. Whether this scenario also applies to neuroblastoma (NB), the most common extracranial solid childhood tumor, is not known. Here, we demonstrate for the first time a prognostic relevance of HO-1 expression in samples from NB patients and show that targeting of HO-1 prevents both cancer resistance against cellular stress and immune escape in the syngeneic NXS2 A/J mouse model of NB. High HO-1 RNA expression in NB tissues emerged as unfavorable prognostic marker, in particular for patients older than 18 months as indicated by univariate as well as multivariate survival probability analyses including disease stage and MYCN status. On the basis of this observation we aimed to target HO-1 by systemic as well as tumor-specific zinc protoporphyrin-mediated HO-1 suppression in a syngeneic immunocompetent NB mouse model. This resulted in 50% reduction of primary tumor growth and a suppression of spontaneous liver metastases. Importantly, HO-1 inhibition abrogated immune cell paralysis affecting CD4 and CD8 T-effector cells. This in turn reverted HO-1-dependent immune escape mechanisms in NB by increasing NB apoptosis and improved DC maturation. In summary, HO-1 emerges as a novel immune regulator in NB and emerges as a promising target for the development of therapeutic approaches.
authors.affiliation: Laboratory of Pediatric Immunotherapy, Department of Pediatrics, Medical Faculty, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany.|Department of Pediatric Oncology, University of Leipzig, Leipzig, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Fest
authors.affiliation: Laboratory of Pediatric Immunotherapy, Department of Pediatrics, Medical Faculty, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany.|Department of Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany.
authors.forename: Rocio
authors.initials: R
authors.lastname: Soldati
authors.affiliation: Department of Pediatric Oncology, University of Leipzig, Leipzig, Germany.
authors.forename: Nina M
authors.initials: NM
authors.lastname: Christiansen
authors.affiliation: Department of Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Zenclussen
authors.affiliation: Laboratory of Pediatric Immunotherapy, Department of Pediatrics, Medical Faculty, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany.|Department of Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Kilz
authors.affiliation: Laboratory of Pediatric Immunotherapy, Department of Pediatrics, Medical Faculty, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany.|Department of Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany.
authors.forename: Elisa
authors.initials: E
authors.lastname: Berger
authors.affiliation: Department of Pediatric Oncology, University of Leipzig, Leipzig, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Starke
authors.affiliation: Department of Pediatrics and Pediatric Hematology/Oncology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Holger N
authors.initials: HN
authors.lastname: Lode
authors.affiliation: Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Engel
authors.affiliation: Department of Experimental Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Zenclussen
authors.affiliation: Department of Pediatric Oncology, University of Leipzig, Leipzig, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Christiansen
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D051547:Heme Oxygenase-1 / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D051379:Mice; D009447:Neuroblastoma / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D011379:Prognosis; D016016:Proportional Hazards Models; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D014408:Biomarkers, Tumor; D051547:Heme Oxygenase-1
keywords: HO-1; immune regulation; neuroblastoma; prognosis