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.
Highlights
Natural killer (NK) cells play a key role in non-specific immune response in different cancers, including pancreatic cancer
Pancreatic cancer cells altered the percentages of surface receptors and cytotoxic granules in NK cells Nine surface receptors (CD16, NKG2D, DNAM-1, NKp30, NKp44, NKp46, NKp80, KIR3DL1, and KIR2DL1/DS1) and two cytotoxic granules (Perforin and Granzyme-B) had been selected for investigation
Their levels and the percentages of NK cells positive for each of these proteins were determined after the NK cells had been cultured alone or with hTERT-HPNE, BxPc-3 or SW1990 cells (Figure 1)
Summary
Natural killer (NK) cells play a key role in non-specific immune response in different cancers, including pancreatic cancer. Pancreatic cancer is one of the most common gastrointestinal malignancies worldwide and is the fifth leading cause of cancer-related deaths [1] It is characterized by rapid progression and intrinsic and acquired drug resistance [2]. Pancreatic cancer is difficult to diagnose in its early stages, the rate of surgical resection is NK cells are key components in the innate immune system, acting as the first line of defense in the body. They are a type of cytotoxic lymphocyte that mediate a pro-inflammatory response and are closely associated with the progression of cancer, including pancreatic cancer [7]. Cancer cells have been shown to induce NK cell dysfunction via downregulation of specific activating surface receptors (e.g. NKG2D), natural cytotoxicity receptors (NCR) [14], cytotoxic granules (e.g. Perforin and Granzyme B) [15], decreased secretion of cytokines (e.g. TNF-α and IFN-γ) [16] and upregulation of inhibitory surface receptors (e.g. KIR3DL1 and KIR2DL1/DS1) [17,18], the underlying mechanisms are largely unknown
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