Abstract

BACKGROUND:Natural killer (NK) cells play a key role innon-specific immune response in different cancers, including pancreatic cancer.However the anti-tumor effect of NK cells decreases during pancreatic cancerprogression. The regulatory pathways by which NK cells facilitate tumor immuneescape are unclear, therefore our purpose was to investigate the roles of thecontributory factors.

METHODS:NK cells isolated from fresh healthy peripheralblood were co-cultured with normal human pancreatic ductal cells hTERT-HPNE andhuman pancreatic cancer cell lines SW1990 and BxPc-3 in vitro. Then NK cellfunction was determined by Flow cytometric analysis of surface receptors andcytotoxic granules in NK cells, NK cell apoptosis and cytotoxicity, andEnzyme-linked immunosorbent assay of cytokines. Expression level of MMP-9, IDOand COX-2 in hTERT-HPNE and SW1990 cells were detected by quantitative RT-PCR.Statistical differences between data groups were determined by independentt-tests using SPSS 19.0 software.

RESULTS:Our results showed that NK cell function wassignificantly downregulated following exposure to pancreatic cancer cellscompared to normal pancreatic cells, as demonstrated by lower expressions ofactivating surface receptors (NKG2D, DNAM-1, NKp30 and NKp46) and cytotoxicgranules (Perforin and Granzyme B); decreased secretion of cytokines (TNF-α andIFN-γ); and reduced cytotoxicity against myelogenous leukemia K562 cells.Further investigations revealed that MMP-9 and IDO may be implicated in SW1990cell-induced NK cell dysfunction by facilitating tumor immune evasion. Blockadeby TIMP-1 and/or 1-MT could partially restore NK function.

CONCLUSIONS:Taken together, elevation of MMP-9 and IDO inducedby pancreatic cancer cells mediates NK cell dysfunction. Our findings couldcontribute to the development of NK cell-based immunotherapy in patients withpancreatic cancer.