title: Modification of dendritic cells with interferon-gamma-inducible protein-10 gene to enhance vaccine potency.
abstract: BACKGROUND
  Dendritic cell (DC)-based vaccines have become a promising modality in cancer immunotherapy. However, their ability to initiate tumor antigen-specific T cell immunity is limited in various negative-feedback mechanisms. The rapid down-regulation of chemokines, such as the interferon inducible protein of 10 kDa (IP-10), which chemoattracts activated antigen-specific CD8+ T cells, would represent negative-feedback regulation. Therefore, we attempted to improve DC vaccine potency by introducing the IP-10 gene retrovirally aiming to replenish the chemoattractive activity of DCs.
  
  
  METHODS
  We introduced IP-10 gene into DC2.4 cells, referred to as DC-IP10, using a retroviral system. Nonsecretable mIP-10-expressing DCs (DC-mIP10) were also prepared to evaluate the effects of secretion in IP-10-mediated modulation of DC biology. Additionally, in vitro and in vivo activation of antigen-specific T lymphocytes and in vivo anti-tumor effects induced by DC-IP10 or DC-mIP10 were determined.
  
  
  RESULTS
  The modification of DC2.4 cells with the IP-10 gene resulted in the secretion of functionally chemoattractive IP-10 and, unexpectedly, a significant up-regulation of surface expression in co-stimulatory molecules, such as CD40 and CD80, compared to that of DCs with vector control (DC-no insert). DC-mIP10 also displayed the partially matured phenotypes but failed to recruit antigen-specific T cells in an in vitro cell culture system. Consistently, DC-IP10 generated more tumor antigen-specific CD8+ T cells and stronger anti-tumor effects in vaccinated mice than did control DCs and DC-mIP10.
  
  
  CONCLUSIONS
  The results obtained provide the groundwork for a future clinical translation of the chemokine-based genetic modification of DCs to increase their vaccine potency.
authors.affiliation: Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, South Korea.
authors.forename: Tae Heung
authors.initials: TH
authors.lastname: Kang
authors.forename: Hyun Cheol
authors.initials: HC
authors.lastname: Bae
authors.forename: Seok-Ho
authors.initials: SH
authors.lastname: Kim
authors.forename: Su Hong
authors.initials: SH
authors.lastname: Seo
authors.forename: Sang Wook
authors.initials: SW
authors.lastname: Son
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Choi
authors.forename: Seung-Yong
authors.initials: SY
authors.lastname: Seong
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Kim
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000096:biosynthesis; D019013:CD40 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology* / Q000378:metabolism / Q000627:therapeutic use; D018929:Cell Culture Techniques; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000096:biosynthesis* / Q000235:genetics* / Q000276:immunology; D002630:Chemotactic Factors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D008213:Lymphocyte Activation; D051379:Mice; D012190:Retroviridae; D014161:Transduction, Genetic; D015854:Up-Regulation
chemical_list: D018122:B7-1 Antigen; D019013:CD40 Antigens; D019496:Cancer Vaccines; D054357:Chemokine CXCL10; D002630:Chemotactic Factors