title: Epigenetic modulation enhances the therapeutic effect of anti-IL-13R(alpha)2 antibody in human mesothelioma xenografts.
abstract: OBJECTIVE
  The interleukin-13 receptor α2 (IL-13Rα2) is expressed by a variety of human malignant cells. Here, we have examined the constitutive surface expression and the epigenetic regulation of IL-13Rα2 by human mesothelioma. We have also investigated the therapeutic effect of the DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) and anti-IL-13Rα2 monoclonal antibody on mesothelioma xenografts.
  
  
  METHODS
  Cell surface expression of IL-13Rα2 by various lung carcinomas was analyzed using flow cytometry. Therapeutic effects of anti-IL-13Rα2 and 5-aza-dC were investigated using antibody-dependent cellular cytotoxicity and proliferation assays and by monitoring the survival of mesothelioma-bearing mice.
  
  
  RESULTS
  We found that human malignant mesotheliomas expressed surface IL-13Rα2 on their surface and that it was upregulated by treatment with 5-aza-dC. This augmented expression of IL-13Rα2 resulted in growth inhibition of the mesothelioma cells when cocultured with anti-IL-13Rα2 and effector cells, such as splenocytes and peritoneal exudate cells. The growth inhibition of mesothelioma cells was mediated by IFN-γ that was only detected in the supernatant when effector cells were exposed to 5-aza-dC-treated tumors in the presence of anti-IL-13Rα2. Compared with the control or either regimen alone, in vivo administration of anti-IL-13Rα2 in combination with 5-aza-dC significantly prolonged the survival of mice with mesothelioma xenografts.
  
  
  CONCLUSIONS
  These observations indicate a promising role for IL-13Rα2 as a target for antibody treatment in malignant mesothelioma, and, in combination with epigenetic regulation by a DNA methylation inhibitor, suggest the potential for a novel strategy to enhance therapeutic potency.
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Takenouchi
authors.forename: Sachie
authors.initials: S
authors.lastname: Hirai
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakuragi
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hamada
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kato
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000627:therapeutic use; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D000077209:Decitabine; D004357:Drug Synergism; D044127:Epigenesis, Genetic / Q000187:drug effects* / Q000502:physiology; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D007167:Immunotherapy; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000037:antagonists & inhibitors / Q000276:immunology*; D008654:Mesothelioma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000964:Antimetabolites, Antineoplastic; D053663:Interleukin-13 Receptor alpha2 Subunit; D000077209:Decitabine; D001374:Azacitidine