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ID: 453 (Conflict of Interest: K)

Exosomen des Tumors hemmen die Funktion der natürlichen Killerzellen (NK) im Pankreaskarzinom

J.Zhao1, H. A.Schlößer1, M.Thelen1, Z.Wang1, J.Qin1, J.Li1, F.Popp1, M. C.Popp1, H.Alakus1, S.-H.Chon1, K.-W.Jauch2, C. J.Bruns1, Y.Zhao1
1Uniklinik Köln, Köln
2Klinikum der Universität München Großhadern, München

Einleitung

Pancreatic cancer is one of the most lethal malignancies in the world. More than 50% of patients are diagnosed with late-stage disease. Exosomes are microvesicles smaller than 150 nm in diameter, which are released by multiple cell types and contain functional various molecules, including proteins, nucleic acids and lipids. Tumor-derived exosomes have been shown to promote cancer progression and metastasis. Besides, many studies have found tumor-derived exosomes displayed increased immunosuppressive functions. Our group are currently investigating the effect of pancreatic cancer-derived exosomes on natural killer (NK) cells.

Material und Methoden

Exosomes was isolated from pancreatic cancer cell line supernatant by ultracentrifugation. Cancer derived exosomes was verified and quantified by western blot, Nanoparticle tracking analysis and electron microscopy. The effects of tumor-derived exosomes on NK cells were investigated by flow cytometry, immunofluorescence and functional assay. PBMC and serum samples from patients with pancreatic cancer and PBMC and healthy individuals were analyzed by flow cytometry and ELISA.

Ergebnisse

Pancreatic cancer cell-derived exosomes with diameters of 30-150 display the surface markers CD9, CD63, CD81, etc. Pancreatic cancer-derived exosomes can be taken up by NK cells. NK cells treated with pancreatic cancer-derived exosomes showed downregulated NK cell activating receptors (NKG2D), dysregulated metabolism and suppressed anti-tumor ability. PDAC-derived exosomes suppress NK cell functions through the phosphorylation of SMAD2/3. In clinical perspectives, we found that serum exosomal TGF-β1 was elevated in patients with PDAC compared to healthy individuals.

Schlussfolgerung

Pancreatic cancer inhibits antitumor activities of NK cells via secretion of exosomes. Tumor-derived exosomes carry immunosuppressive factors in PDAC, such as TGF-β1. Thus, tumor-derived exosomes induce NK cell exhaustion, which may lead to distant metastasis of pancreatic cancer.