title: Radiation combined with hyperthermia induces HSP70-dependent maturation of dendritic cells and release of pro-inflammatory cytokines by dendritic cells and macrophages.
abstract: OBJECTIVE
  Hyperthermia (HT) treatment of cancer patients was revived over the last years and has been proven to be beneficiary for many cancer entities when applied temperature controlled in multimodal treatments. We examined whether a combination of ionizing irradiation (X-ray) and HT (41.5°C; 1 h) can induce the release of heat shock protein (HSP) 70 by tumor cells and thereby lead to the activation of dendritic cells and macrophages.
  
  
  METHODS
  Extracellular HSP70 was detected in supernatants (SN) of treated colorectal tumor cells by ELISA. Maturation of dendritic cells (DC) after contact with the SN was measured by flow-cytometry. Phagocytosis assays were conducted to get hints about the immune stimulating potential of the tumor cells after the respective treatments.
  
  
  RESULTS
  An increased surface expression of HSP70 was observed after X-ray or X-ray plus HT while the amount of extracellular HSP70 was only increased when HT was given additionally. A high up-regulation of the co-stimulation molecule CD80 and the chemokine receptor CCR7 on DC was measured after contact with SN of X-ray plus HT treated cells. This was dependent on extracellular HSP70. Combined treatments further led to significantly increased phagocytosis rates of macrophages and DC and increased pro-inflammatory cytokine (IL-8 and IL-12) secretion.
  
  
  CONCLUSIONS
  X-ray combined with HT induces HSP70 dependent activation of immune cells and might generate a tumor microenvironment beneficial for cure.
authors.affiliation: Department of Radiation Oncology, Friedrich-Alexander University of Erlangen-Nürnberg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Schildkopf
authors.forename: Benjamin
authors.initials: B
authors.lastname: Frey
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Ott
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Rubner
authors.forename: Gabriele
authors.initials: G
authors.lastname: Multhoff
authors.forename: Rolf
authors.initials: R
authors.lastname: Sauer
authors.forename: Rainer
authors.initials: R
authors.lastname: Fietkau
authors.forename: Udo S
authors.initials: US
authors.lastname: Gaipl
mesh_terms: D000818:Animals; D015179:Colorectal Neoplasms / Q000473:pathology / Q000628:therapy; D003131:Combined Modality Therapy; D016207:Cytokines / Q000378:metabolism* / Q000528:radiation effects; D003713:Dendritic Cells / Q000378:metabolism* / Q000528:radiation effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism* / Q000528:radiation effects; D006801:Humans; D007036:Hypothermia, Induced; D018664:Interleukin-12 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011839:Radiation, Ionizing; D018709:Statistics, Nonparametric; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000528:radiation effects; D015854:Up-Regulation / Q000528:radiation effects
chemical_list: D016207:Cytokines; D018840:HSP70 Heat-Shock Proteins; D016209:Interleukin-8; D018664:Interleukin-12