title: Activation of the human immune system via toll-like receptors by the oncolytic parvovirus H-1.
abstract: This study aimed to investigate the function of toll-like receptors (TLRs) during oncolytic parvovirus H-1 (H-1PV)-induced human immune responses. First, the role of TLRs in the activation of the NFκB transcription factor was characterized; second, the immunologic effects of H-1PV-induced tumor cell lysates (TCL) on human antitumor immune responses were evaluated. A human ex vivo model was used to study immune responses with dendritic cells (DCs). Human embryonic kidney cells (HEK293) transfected to stably express TLRs were used as potential human DC equivalents to further investigate the role of specific TLRs during immune activation. TLR3 and TLR9 were activated by H-1PV infection, which correlated with NFκB translocation to the nucleus and a reduced cytoplasmic IκB expression. Using a TLR-signaling reporter plasmid (pNiFty-Luc), NFκB activity was increased following H-1PV infection. In addition, human DCs coincubated with H-1PV-induced TCL demonstrated increased TLR3 and TLR9 expression. These data suggest that H-1PV-induced TCL stimulate human DCs at least in part through TLR-dependent signaling pathways. Thus, DC maturation occurred through exposure to H-1PV-induced TCL through TLR-signaling leading to NFκB-dependent activation of the adaptive immune system as indicated by the increased expression of CD86, TLR3 and TLR9. Furthermore, the transcription of various cytokines indicates the activation of immune response, therefore the production of the proinflammatory cytokine TNF-α was determined. Here, H-1PV-induced TCL significantly enhanced the TNF-α level by DCs after coculture. H-1PV oncolytic virotherapy enhances immune priming by different effects on DCs and generates antitumor immunity. These findings potentially offer a new approach to tumor therapy.
authors.affiliation: First Department of Internal Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Sieben
authors.forename: Petra
authors.initials: P
authors.lastname: Schäfer
authors.forename: Christiane
authors.initials: C
authors.lastname: Dinsart
authors.forename: Peter R
authors.initials: PR
authors.lastname: Galle
authors.forename: Markus
authors.initials: M
authors.lastname: Moehler
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology / Q000821:virology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D052661:H-1 parvovirus / Q000276:immunology*; D006801:Humans; D007107:Immune System; D007668:Kidney / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000276:immunology*; D010322:Parvoviridae Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha