title: TNF-α and tumor lysate promote the maturation of dendritic cells for immunotherapy for advanced malignant bone and soft tissue tumors.
abstract: BACKGROUND
  Dendritic cells (DCs) play a pivotal role in the immune system. There are many reports concerning DC-based immunotherapy. The differentiation and maturation of DCs is a critical part of DC-based immunotherapy. We investigated the differentiation and maturation of DCs in response to various stimuli.
  
  
  METHODS
  Thirty-one patients with malignant bone and soft tissue tumors were enrolled in this study. All the patients had metastatic tumors and/or recurrent tumors. Peripheral blood mononuclear cells (PBMCs) were suspended in media containing interleukin-4 (IL-4) and granulocyte-macrophage colony stimulating factor (GM-CSF). These cells were then treated with or without 1) tumor lysate (TL), 2) TL + TNF-α, 3) OK-432. The generated DCs were mixed and injected in the inguinal or axillary region. Treatment courses were performed every week and repeated 6 times. A portion of the cells were analyzed by flow cytometry to determine the degree of differentiation and maturation of the DCs. Serum IFN-γ and serum IL-12 were measured in order to determine the immune response following the DC-based immunotherapy.
  
  
  RESULTS
  Approximately 50% of PBMCs differentiated into DCs. Maturation of the lysate-pulsed DCs was slightly increased. Maturation of the TL/TNF-α-pulsed DCs was increased, commensurate with OK-432-pulsed DCs. Serum IFN-γ and serum IL-12 showed significant elevation at one and three months after DC-based immunotherapy.
  
  
  CONCLUSIONS
  Although TL-pulsed DCs exhibit tumor specific immunity, TL-pulsed cells showed low levels of maturation. Conversely, the TL/TNF-α-pulsed DCs showed remarkable maturation. The combination of IL-4/GM-CSF/TL/TNF-α resulted in the greatest differentiation and maturation for DC-based immunotherapy for patients with bone and soft tissue tumors.
authors.affiliation: Department of Orthopaedic Surgery, Kanazawa University School of Medicine, Kanazawa, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Miwa
authors.forename: Hideji
authors.initials: H
authors.lastname: Nishida
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Tanzawa
authors.forename: Munetomo
authors.initials: M
authors.lastname: Takata
authors.forename: Akihiko
authors.initials: A
authors.lastname: Takeuchi
authors.forename: Norio
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Shirai
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Hayashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kimura
authors.forename: Kentaro
authors.initials: K
authors.lastname: Igarashi
authors.forename: Eishiro
authors.initials: E
authors.lastname: Mizukoshi
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Nakamoto
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuchiya
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001859:Bone Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D002454:Cell Differentiation; D002648:Child; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D018664:Interleukin-12 / Q000494:pharmacology / Q000627:therapeutic use; D015847:Interleukin-4 / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010844:Picibanil / Q000494:pharmacology / Q000627:therapeutic use; D012983:Soft Tissue Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D015847:Interleukin-4; D010844:Picibanil; D016178:Granulocyte-Macrophage Colony-Stimulating Factor