title: 5-Fluorouracil and interleukin-2 immunochemotherapy enhances immunogenicity of non-small cell lung cancer A549 cells through upregulation of NKG2D ligands.
abstract: BACKGROUND
  The aim of this study was to investigate the anti-cancer effects and mechanisms of immunochemotherapy of 5-fluorouracil (5-FU) and interleukin-2 (IL-2) on non-small cell lung cancer (NSCLC) A549 cells.
  
  
  METHODS
  In order to detect whether 5-FU+IL-2 could effectively inhibit tumor growth in vivo, we established an A549-bearing nude mouse model. The cytotoxicity of natural killer (NK) cells was evaluated using a standard chromium release assay. To evaluate the relevance of NK cells in 5-FU+IL-2- mediated tumor inhibitory effects, we depleted NK cells in A549-bearing mice by injecting anti-asialo-GM-1 antibodies. Effects of 5-FU+IL-2 on the expression and promoter activity of NKG2D ligands (MICA/MICB) in A549 cells in vitro were also assessed.
  
  
  RESULTS
  In A549-bearing nude mice, combination therapy significantly inhibited tumor growth in comparison with monotherapy with 5-FU or IL-2 and enhanced the recognition and lysis of tumor cells by NK cells. Further study of mechanisms showed that NK cells played a vital role in the anticancer immune response of 5-FU+IL-2 immunochemotherapy. In addition, the combination therapy synergistically stimulated the expression and promoter activity of MICA/MICB.
  
  
  CONCLUSIONS
  5-FU and IL-2 immunochemotherapy significantly inhibited tumor growth and activated NK cytotoxicity in vivo, and these effects were partly impaired after depleting NK cells in tumor-bearing mice. Combination treatment of 5-FU and IL-2 upregulated the expression and the promoter activity of MICA/MICB in A549 cells, which enhanced the recognition of A549 cells by NK cells. All of the data indicated that immunochemotherapy of 5-FU and IL-2 may provide a new treatment option for patients with lung cancer.
authors.affiliation: Institute of Frontier Medical Science, Jilin University, Changchun, Jilin, China E-mail : zhang_xingyi28@163.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: Wen-Jia
authors.initials: WJ
authors.lastname: Wang
authors.forename: Jin-Nan
authors.initials: JN
authors.lastname: Zhang
authors.forename: Xing-Yi
authors.initials: XY
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000276:immunology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D005472:Fluorouracil / Q000627:therapeutic use*; D058851:GPI-Linked Proteins / Q000096:biosynthesis; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic / Q000235:genetics; D015533:Transcriptional Activation; D014183:Transplantation, Heterologous; D015854:Up-Regulation
chemical_list: D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; D007376:Interleukin-2; C099187:MHC class I-related chain A; C098080:MICB antigen; C423230:ULBP2 protein, human; D005472:Fluorouracil