title: Potent immunotherapy against well-established thymoma using adoptively transferred transgene IL-6-engineered dendritic cell-stimulated CD8+ T-cells with prolonged survival and enhanced cytotoxicity.
abstract: BACKGROUND
  Adoptive transfer of CD8(+) T-cells specific for tumor-antigens is an attractive strategy for anti-tumor therapy. In the present study, the subsets TA and TB were used to represent the population of CD8(+) T cells generated by culturing the respective cells with irradiated dendritic cells (DCs) pulsed with ovalbumin (OVA) protein and transfected with adenoviral vector constructs as described.
  
  
  METHODS
  Naïve OVA specific CD8(+) T cells were isolated from the spleen of OVA-specific T-cell receptor transgenic OTI mice. The subsets TA and TB were then generated by in vitro activating the population of CD8(+) T cells with OVA-pulsed DCs transfected with IL-6-expressing adenoviral vector (AdVIL-6 ) or the control vector (AdVNull ). To assess their in vivo immunotherapeutic effects, TA - or TB -cells were intravenously transferred into C57BL/6 mice bearing EG7 thymoma (6-8 mm in diameter).
  
  
  RESULTS
  TA -cells displayed a higher level of expression of CD62 l, IL-7R, FasL, perforin and CCR6, and also exhibited more potent in vitro cytotoxicity to OVA-expressing EG7 thymoma cells via perforin- and Fas/FasL-mediated apoptosis than TB -cells. CD8(+) T-cell survival was kinetically analyzed in C57BL/6 mice transferred with TA - or TB -cells by flow cytometry. We found that the adoptively transferred TA -cells had prolonged survival and enhanced T-cell memory development compared to TB -cells. In addition, TA -, but not TB -cells were able to eradicate well-established EG7 thymomas in all eight tumor-bearing mice.
  
  
  CONCLUSIONS
  Our data suggest that AdVIL-6 -transfected DC-stimulated CD8(+) T cells with potent cytotoxicity and survival advantage may serve as an effective adoptive CD8(+) T-cell immunotherapy strategy for anti-tumor treatment.
authors.affiliation: Cancer Research Cluster, Saskatchewan Cancer Agency, Division of Oncology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Kalpana
authors.initials: K
authors.lastname: Kalyanasundaram Bhanumathy
authors.affiliation: Cancer Research Cluster, Saskatchewan Cancer Agency, Division of Oncology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Bei
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Cancer Research Cluster, Saskatchewan Cancer Agency, Division of Oncology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Cancer Research Cluster, Saskatchewan Cancer Agency, Division of Oncology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Aizhang
authors.initials: A
authors.lastname: Xu
authors.affiliation: College of Life Science, Beijing Institute of Technology, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Tan
authors.affiliation: Cancer Research Cluster, Saskatchewan Cancer Agency, Division of Oncology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Jim
authors.initials: J
authors.lastname: Xiang
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D005822:Genetic Vectors / Q000235:genetics; D016219:Immunotherapy, Adoptive; D015850:Interleukin-6 / Q000235:genetics*; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013945:Thymoma / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D019076:Transgenes / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D015850:Interleukin-6
keywords: EG7 thymoma; adoptive T-cell transfer; cytotoxicity; immunotherapy; memory; survival