title: Vaccination strategy to target lysyl oxidase-like 4 in dendritic cell based immunotherapy for head and neck cancer.
abstract: Overexpression of lysyl oxidase (LOX) is associated with the invasive potential of metastatic breast and head and neck cancer (HNC) cells and reduced metastasis-free and overall survival. Recently, we have demonstrated up-regulation of a new member of the LOX family, lysyl oxidase-like 4 (LOXL4), in invasive HNC revealed a significant correlation between LOXL4 expression and local lymph node metastases and higher tumour stages. The objective of this study was to examine whether cellular LOXL4 may provide an effective target for cell-meditated immunotherapy in invasive tumours associated with LOXL4 overexpression. As a feasibility study we expressed LOXL4 mRNA in immature dendritic cells derived from human peripheral blood mononuclear cells (PBMC). LOXL4 protein expression was ascertained using Western blotting and immunocytochemistry with polyclonal rabbit anti-LOXL4 antibody. The successfully transfected immature dendritic cells (DCs) were induced to mature with GM-CSF, IL-4, IL-1beta, TNF-alpha, IL-6, and PGE2, and then used to stimulate T cell enriched non-adherent fraction of PBMC. LOXL4 specific T cell stimulation induced cytotoxic T lymphocyte (CTL) response was monitored using IFN-gamma secretion from the non-adherent PBMC fraction exposed to mature, LOXL4 transfected DCs acting as the antigen presenting target cells. LOXL4-DC stimulated T cells produced higher IFN-gamma secretion compared to unstimulated T cells and T cells stimulated with untransfected DCs, in the presence of the pan-DR-epitope (PADRE). These initial results demonstrated the potential for LOXL4-transfected DCs to serve as efficient tumour vaccine and support their suitability as a vaccination strategy applicable to cancer patients with tumour specific up-regulation of LOXL4.
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University of Kiel, Arnold-Heller-Strasse 14, Kiel, Germany. jweise@hno.uni-kiel.de
authors.forename: Jan Bernd
authors.initials: JB
authors.lastname: Weise
authors.forename: Katalin
authors.initials: K
authors.lastname: Csiszar
authors.forename: Stefan
authors.initials: S
authors.lastname: Gottschlich
authors.forename: Markus
authors.initials: M
authors.lastname: Hoffmann
authors.forename: André
authors.initials: A
authors.lastname: Schmidt
authors.forename: Ute
authors.initials: U
authors.lastname: Weingartz
authors.forename: Ilse
authors.initials: I
authors.lastname: Adamzik
authors.forename: Axel
authors.initials: A
authors.lastname: Heiser
authors.forename: Dieter
authors.initials: D
authors.lastname: Kabelitz
authors.forename: Petra
authors.initials: P
authors.lastname: Ambrosch
authors.forename: Tibor
authors.initials: T
authors.lastname: Görögh
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000378:metabolism*; D000951:Antigens, Neoplasm / Q000737:chemistry; D019496:Cancer Vaccines / Q000737:chemistry; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism; D000939:Epitopes / Q000737:chemistry; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000276:immunology* / Q000628:therapy; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D017780:Malaria Vaccines / Q000737:chemistry*; D008249:Protein-Lysine 6-Oxidase; D012333:RNA, Messenger / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D000939:Epitopes; D017780:Malaria Vaccines; C401223:PADRE 45; D012333:RNA, Messenger; D007371:Interferon-gamma; D000594:Amino Acid Oxidoreductases; C445682:LOXL4 protein, human; D008249:Protein-Lysine 6-Oxidase