title: Combination doxorubicin and interferon-α therapy stimulates immunogenicity of murine pancreatic cancer Panc02 cells via up-regulation of NKG2D ligands and MHC class I.
abstract: BACKGROUND
  Pancreatic adenocarcinoma is a malignant gastrointestinal cancer with significant morbidity and mortality. Despite severe side effects of chemotherapy, the use of immunotherapy combined with chemotherapy has emerged as a common clinical treatment. In this study, we investigated the efficacy of the combined doxorubicin and interferon-α (IFN-α) therapy on murine pancreatic cancer Panc02 cells in vitro and in vivo and underlying mechanisms.
  
  
  METHODS
  A Panc02-bearing mouse model was established to determine whether doxorubicin and interferon-α (IFN-α) could effectively inhibit tumor growth in vivo. Cytotoxicity of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) was evaluated using a standard LDH release assay. To evaluate the relevance of NK cells and CD8 T cells to the combination therapy-mediated anti-tumor effects, they were depleted in tumor-bearing mice by injecting anti-asialo-GM-1 antibodies or anti-CD8 antibodies, respectively. Finally, the influence of doxorubicin+interferon-α (IFN-α) on the ligands of NK and T cells was assessed by flow cytometry.
  
  
  RESULTS
  The combination therapy group demonstrated a significant inhibition of growth of Panc02 in vivo, resulting from activated cytotoxicity of NK cells and CTLs. Depleting CD8 T cells or NK cells reduced the anticancer effects mediated by immunochemotherapy. Furthermore, the doxorubicin+IFN-a treatment increased the expression of major histocompatibility complex class I (MHC I) and NKG2D ligands on Panc02 cells, suggesting that the combined therapy may be a potential strategy for enhancing immunogenicity of tumors. All these data indicate that the combination therapy using doxorubicin and interferon-α (IFN-α) may be a potential strategy for treating pancreatic adenocarcinoma.
authors.affiliation: Institute of Pharmacy, Jilin University, Changchun, Jilin, China E-mail : zjghospital@sina.com.
authors.forename: Wen-Jia
authors.initials: WJ
authors.lastname: Wang
authors.forename: Si-Hao
authors.initials: SH
authors.lastname: Qin
authors.forename: Ji-Wei
authors.initials: JW
authors.lastname: Zhang
authors.forename: Yue-Yao
authors.initials: YY
authors.lastname: Jiang
authors.forename: Jin-Nan
authors.initials: JN
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002352:Carrier Proteins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D007167:Immunotherapy / Q000379:methods; D016898:Interferon-alpha / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology; D008212:Lymphocyte Depletion; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis*; D009368:Neoplasm Transplantation; D034521:Nuclear Matrix-Associated Proteins / Q000096:biosynthesis; D029543:Nucleocytoplasmic Transport Proteins / Q000096:biosynthesis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D015395:Histocompatibility Antigens Class I; D016898:Interferon-alpha; C527086:Klrk1 protein, mouse; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034521:Nuclear Matrix-Associated Proteins; D029543:Nucleocytoplasmic Transport Proteins; C490521:Rae1 protein, mouse; C468260:UL16 binding protein 1, mouse; D004317:Doxorubicin