title: Elevation of MMP-9 and IDO induced by pancreatic cancer cells mediates natural killer cell dysfunction.
abstract: BACKGROUND
  Natural killer (NK) cells play a key role in non-specific immune response in different cancers, including pancreatic cancer. However the anti-tumor effect of NK cells decreases during pancreatic cancer progression. The regulatory pathways by which NK cells facilitate tumor immune escape are unclear, therefore our purpose was to investigate the roles of the contributory factors.
  
  
  METHODS
  NK cells isolated from fresh healthy peripheral blood were co-cultured with normal human pancreatic ductal cells hTERT-HPNE and human pancreatic cancer cell lines SW1990 and BxPc-3 in vitro. Then NK cell function was determined by Flow cytometric analysis of surface receptors and cytotoxic granules in NK cells, NK cell apoptosis and cytotoxicity, and Enzyme-linked immunosorbent assay of cytokines. Expression level of MMP-9, IDO and COX-2 in hTERT-HPNE and SW1990 cells were detected by quantitative RT-PCR. Statistical differences between data groups were determined by independent t-tests using SPSS 19.0 software.
  
  
  RESULTS
  Our results showed that NK cell function was significantly downregulated following exposure to pancreatic cancer cells compared to normal pancreatic cells, as demonstrated by lower expressions of activating surface receptors (NKG2D, DNAM-1, NKp30 and NKp46) and cytotoxic granules (Perforin and Granzyme B); decreased secretion of cytokines (TNF-α and IFN-γ); and reduced cytotoxicity against myelogenous leukemia K562 cells. Further investigations revealed that MMP-9 and IDO may be implicated in SW1990 cell-induced NK cell dysfunction by facilitating tumor immune evasion. Blockade by TIMP-1 and/or 1-MT could partially restore NK function.
  
  
  CONCLUSIONS
  Taken together, elevation of MMP-9 and IDO induced by pancreatic cancer cells mediates NK cell dysfunction. Our findings could contribute to the development of NK cell-based immunotherapy in patients with pancreatic cancer.
authors.forename: Yun-Peng
authors.initials: YP
authors.lastname: Peng
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Zhang
authors.forename: Wen-biao
authors.initials: WB
authors.lastname: Liang
authors.forename: Min
authors.initials: M
authors.lastname: Tu
authors.forename: Zi-Peng
authors.initials: ZP
authors.lastname: Lu
authors.forename: Ji-Shu
authors.initials: JS
authors.lastname: Wei
authors.forename: Kui-Rong
authors.initials: KR
authors.lastname: Jiang
authors.forename: Wen-Tao
authors.initials: WT
authors.lastname: Gao
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Wu
authors.forename: Ze-Kuan
authors.initials: ZK
authors.lastname: Xu
authors.affiliation: Department of General Surgery, The first Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, People's Republic of China. miaoyi@njmu.edu.cn.
authors.forename: Yi
authors.initials: Y
authors.lastname: Miao
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D017209:Apoptosis / Q000276:immunology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism
chemical_list: D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D011956:Receptors, Cell Surface; D020780:Matrix Metalloproteinase 9