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BMC Cancer

, 14:738

Infection, immunity and cancer vaccines

Abstract

BackgroundNatural 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.

MethodsNK 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.

ResultsOur 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.

ConclusionsTaken 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.

KeywordsPancreatic cancer Natural killer cell dysfunction MMP-9 IDO AbbreviationsNK cellNatural killer cell

MMP-9Matrix metallopeptidase 9

IDOIndoleamine 2, 3-dioxygnase

MSCMesenchymal stem cells

NCRNatural cytotoxicity receptors

1-MT1-Methyl-DL-tryptopan

TIMP-1Tissue inhibitor of metalloproteinases 1

PBMCPeripheral blood mononuclear cells

ELISAEnzyme-linked immunosorbent assay

qRT-PCRQuantitative real-time reverse-transcription polymerase chain reaction.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-14-738 contains supplementary material, which is available to authorized users.

Yun-Peng Peng, Jing-Jing Zhang contributed equally to this work.

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Autor: Yun-Peng Peng - Jing-Jing Zhang - Wen-biao Liang - Min Tu - Zi-Peng Lu - Ji-Shu Wei - Kui-Rong Jiang - Wen-Tao Gao - Jun-L

Fuente: https://link.springer.com/



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