Oncotarget

Research Papers:

Gemcitabine inhibits immune escape of pancreatic cancer by down regulating the soluble ULBP2 protein

Xiansheng Lin, Mei Huang, Fang Xie, Hangcheng Zhou, Ji Yang and Qiang Huang _

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Oncotarget. 2016; 7:70092-70099. https://doi.org/10.18632/oncotarget.11780

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Abstract

Xiansheng Lin1,2,*, Mei Huang1,2,*, Fang Xie1, Hangcheng Zhou3, Ji Yang1, Qiang Huang1,2

1Department of General Surgery, Affiliated Provincial Hospital of Anhui Medical University, Hefei, 230001, China

2Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, 230001, China

3Department of Pathology, Affiliated Provincial Hospital of Anhui Medical University, Hefei, 230001, China

*These authors have contributed equally to this work

Correspondence to:

Qiang Huang, email: ahslyyhq2016@163.com

Keywords: pancreatic cancer, gemcitabine, ULBP2, ADAM10, NK cells

Received: June 07, 2016    Accepted: August 15, 2016    Published: September 01, 2016

ABSTRACT

Due to early onset of local invasion and distant metastasis, pancreatic cancer is the most lethal human malignant tumor, with a 5 year survival rate of less than 5%. As a effective chemotherapy drug for pancreatic cancer patients, gemcitabine is reported to inhibit cell proliferation as a nucleotide analog. In this study, we investigated the role of gemcitabine in immune regulation of pancreatic cancer. Our data showed that the level of soluble ULBP2 (sULBP2), a ligand of NKG2D receptor, decreased in the supernatants of pancreatic cancer cell lines when gemcitabine was added, and sULBP2 level correlated with NK92 cells cytotoxicity to pancreatic cancer cell lines. Importantly, our data showed that gemcitabine promoted PANC-1 cells and MIA PaCa-2 immune evasion by reducing ADAM10 expression, a metalloproteinase involved in sULBP2 shedding from cell membrane. Knockdown of ADAM10 clearly downregulated sULBP2 levels in the culture supernatants and cells became more susceptible to NK92 cytotoxicity. Serum samples and tumor samples were obtained from 45 patients with pancreatic ductal adenocarcinoma (PDAC). Statistical analysis showed a significant correlation between the serum level of sULBP2 with ADAM10 expression in PDAC tissues. In conclusion, our data demostrated that gemcitabine inhibits ULBP2 ectodomain shedding through the suppression of ADAM10 and enhance NK cells cytotoxicity by NKG2D-ULBP2 interaction. The results extends our understanding of gemcitabine in the treatment of pancreatic cancer from cell proliferation inhibition to immune regulation.


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