Gemcitabine inhibits immune escape of pancreatic cancer by down regulating the soluble ULBP2 protein.
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.
Department of General Surgery, Affiliated Provincial Hospital of Anhui Medical University, Hefei, 230001, China.|Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, 230001, China.
Xiansheng
X
Lin
Department of General Surgery, Affiliated Provincial Hospital of Anhui Medical University, Hefei, 230001, China.|Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, 230001, China.
Mei
M
Huang
Department of General Surgery, Affiliated Provincial Hospital of Anhui Medical University, Hefei, 230001, China.
Fang
F
Xie
Department of Pathology, Affiliated Provincial Hospital of Anhui Medical University, Hefei, 230001, China.
Hangcheng
H
Zhou
Department of General Surgery, Affiliated Provincial Hospital of Anhui Medical University, Hefei, 230001, China.
Ji
J
Yang
Department of General Surgery, Affiliated Provincial Hospital of Anhui Medical University, Hefei, 230001, China.|Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, 230001, China.
Qiang
Q
Huang
D000072197:ADAM10 Protein / Q000032:analysis / Q000037:antagonists & inhibitors; D000328:Adult; D000368:Aged; D053829:Amyloid Precursor Protein Secretases / Q000032:analysis / Q000037:antagonists & inhibitors; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D058851:GPI-Linked Proteins / Q000032:analysis / Q000037:antagonists & inhibitors; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000032:analysis / Q000037:antagonists & inhibitors; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000276:immunology*; D019139:Tumor Escape / Q000187:drug effects*; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C423230:ULBP2 protein, human; D003841:Deoxycytidine; D053829:Amyloid Precursor Protein Secretases; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000093542:Gemcitabine
ADAM10; NK cells; ULBP2; gemcitabine; pancreatic cancer