Activation of the human immune system via toll‐like receptors by the oncolytic parvovirus H‐1

• Published in: International journal of cancer 2013-06, Vol.132 (11), p.2548-2556
• Main Authors: Sieben, Maike, Schäfer, Petra, Dinsart, Christiane, Galle, Peter R., Moehler, Markus
• Format: Article
• Language: English
• Subjects: Antitumor activity; autonomous parvovirus; Biological and medical sciences; Cancer; Cancer therapies; Cell Nucleus - metabolism; Cells, Cultured; Cytokines - metabolism; Cytoplasm - metabolism; Cytotoxicity, Immunologic; dendritic cells; Dendritic Cells - immunology; Dendritic Cells - pathology; Dendritic Cells - virology; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; H-1 parvovirus - immunology; Humans; Immune System; Immunology; Kidney - immunology; Kidney - metabolism; Kidney - pathology; Medical research; Medical sciences; Melanoma - immunology; Melanoma - metabolism; Melanoma - therapy; NF-kappa B - genetics; NF-kappa B - metabolism; nuclear factor‐kappaB; Oncolytic Virotherapy; Oncolytic Viruses - immunology; Parvoviridae Infections - immunology; Parvoviridae Infections - pathology; Parvoviridae Infections - virology; Parvovirus; Signal Transduction; Toll-Like Receptors - immunology; Toll-Like Receptors - metabolism; toll‐like receptors; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - pharmacology; Tumors
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.27938

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. What's new? Parvovirus H‐1 (H‐1PV) possesses oncolytic properties and is known to activate dendritic immune cells, though the mechanisms of host cell recognition and immune activation are not well characterized. Here, H‐1PV was found to exert its effects through activation of toll‐like receptor 3 (TLR3) and TLR9, leading to enhanced NFκB expression. In H‐1PV‐infected tumor cell lysates, TLR activation led to dendritic cell maturation and immune stimulation. The findings shed light on mechanisms that could impact the development of novel H‐1PV oncolytic therapies.