Full Text:   <2276>

Summary:  <1606>

CLC number: R73-37

On-line Access: 2016-07-06

Received: 2015-11-04

Revision Accepted: 2016-01-22

Crosschecked: 2016-06-18

Cited: 2

Clicked: 3893

Citations:  Bibtex RefMan EndNote GB/T7714


Li-ping Cao


Jiong-huang Chen


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Journal of Zhejiang University SCIENCE B 2016 Vol.17 No.7 P.537-544


Cholangiocarcinoma-derived exosomes inhibit the antitumor activity of cytokine-induced killer cells by down-regulating the secretion of tumor necrosis factor-α and perforin

Author(s):  Jiong-huang Chen, Jian-yang Xiang, Guo-ping Ding, Li-ping Cao

Affiliation(s):  Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China

Corresponding email(s):   caolipingzju@126.com

Key Words:  Cholangiocarcinoma, Tumor-derived exosomes, Cytokine-induced killer cells, Immune escape

Jiong-huang Chen, Jian-yang Xiang, Guo-ping Ding, Li-ping Cao. Cholangiocarcinoma-derived exosomes inhibit the antitumor activity of cytokine-induced killer cells by down-regulating the secretion of tumor necrosis factor-α and perforin[J]. Journal of Zhejiang University Science B, 2016, 17(7): 537-544.

@article{title="Cholangiocarcinoma-derived exosomes inhibit the antitumor activity of cytokine-induced killer cells by down-regulating the secretion of tumor necrosis factor-α and perforin",
author="Jiong-huang Chen, Jian-yang Xiang, Guo-ping Ding, Li-ping Cao",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Cholangiocarcinoma-derived exosomes inhibit the antitumor activity of cytokine-induced killer cells by down-regulating the secretion of tumor necrosis factor-α and perforin
%A Jiong-huang Chen
%A Jian-yang Xiang
%A Guo-ping Ding
%A Li-ping Cao
%J Journal of Zhejiang University SCIENCE B
%V 17
%N 7
%P 537-544
%@ 1673-1581
%D 2016
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1500266

T1 - Cholangiocarcinoma-derived exosomes inhibit the antitumor activity of cytokine-induced killer cells by down-regulating the secretion of tumor necrosis factor-α and perforin
A1 - Jiong-huang Chen
A1 - Jian-yang Xiang
A1 - Guo-ping Ding
A1 - Li-ping Cao
J0 - Journal of Zhejiang University Science B
VL - 17
IS - 7
SP - 537
EP - 544
%@ 1673-1581
Y1 - 2016
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B1500266

Objective: The aim of our study is to observe the impact of cholangiocarcinoma-derived exosomes on the antitumor activities of cytokine-induced killer (CIK) cells and then demonstrate the appropriate mechanism. Methods: tumor-derived exosomes (TEXs), which are derived from RBE cells (human cholangiocarcinoma line), were collected by ultracentrifugation. CIK cells induced from peripheral blood were stimulated by TEXs. Fluorescence-activated cell sorting (FACS) was performed to determine the phenotypes of TEX-CIK and N-CIK (normal CIK) cells. The concentrations of tumor necrosis factor-α (TNF-α) and perforin in the culture medium supernatant were examined by using an enzyme-linked immunosorbent assay (ELISA) kit. A CCK-8 kit was used to evaluate the cytotoxic activity of the CIK cells to the RBE cell line. Results: The concentrations of TNF-α and perforin of the group TEX-CIK were 138.61 pg/ml and 2.41 ng/ml, respectively, lower than those of the group N-CIK 194.08 pg/ml (P<0.01) and 3.39 ng/ml (P<0.05). The killing rate of the group TEX-CIK was 33.35%, lower than that of the group N-CIK (47.35% (P<0.01)). The population of CD3+, CD8+, NK (CD56+), and CD3+CD56+ cells decreased in the TEX-CIK group ((63.2±6.8)%, (2.5±1.0)%, (0.53±0.49)%, (0.45±0.42)%) compared with the N-CIK group ((90.3±7.3)%, (65.7±3.3)%, (4.2±1.2)%, (15.2±2.7)%), P<0.01. Conclusions: Our results suggest that RBE cells-derived exosomes inhibit the antitumor activity of CIK cells by down-regulating the population of CD3+, CD8+, NK (CD56+), and CD3+CD56+ cells and the secretion of TNF-α and perforin. TEX may play an important role in cholangiocarcinoma immune escape.




Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]Apte, M.V., Wilson, J.S., Lugea, A., et al., 2013. A starring role for stellate cells in the pancreatic cancer microenvironment. Gastroenterology, 144(6):1210-1219.

[2]Bretz, N.P., Ridinger, J., Rupp, A.K., et al., 2013. Body fluid exosomes promote secretion of inflammatory cytokines in monocytic cells via Toll-like receptor signaling. J. Biol. Chem., 288(51):36691-36702.

[3]Carswell, E.A., Old, L.J., Kassel, R.L., et al., 1975. An endotoxin-induced serum factor that causes necrosis of tumors. PNAS, 72(9):3666-3670.

[4]Chiba, M., Kimura, M., Asari, S., 2012. Exosomes secreted from human colorectal cancer cell lines contain mRNAs, microRNAs and natural antisense RNAs, that can transfer into the human hepatoma HepG2 and lung cancer A549 cell lines. Oncol. Rep., 28(5):1551-1558.

[5]Ewald, F., Grabinski, N., Grottke, A., et al., 2013. Combined targeting of AKT and mTOR using MK-2206 and RAD001 is synergistic in the treatment of cholangiocarcinoma. Int. J. Cancer, 133(9):2065-2076.

[6]Garcia, K.C., Scott, C.A., Brunmark, A., et al., 1996. CD8 enhances formation of stable T-cell receptor/MHC class I molecule complexes. Nature, 384(6609):577-581.

[7]Hongeng, S., Petvises, S., Worapongpaiboon, S., et al., 2003. Generation of CD3+CD56+ cytokine-induced killer cells and their in vitro cytotoxicity against pediatric cancer cells. Int. J. Hematol., 77(2):175-179.

[8]Khan, S.A., Thomas, H.C., Davidson, B.R., et al., 2005. Cholangiocarcinoma. Lancet, 366(9493):1303-1314.

[9]Liu, C.C., Walsh, C.M., Young, J.D., 1995. Perforin: structure and function. Immunol. Today, 16(4):194-201.

[10]Lu, P.H., Negrin, R.S., 1994. A novel population of expanded human CD3+CD56+ cells derived from T cells with potent in vivo antitumor activity in mice with severe combined immunodeficiency. J. Immunol., 153(4):1687-1696.

[11]Ma, Y., Xu, Y.C., Tang, L., et al., 2012. Cytokine-induced killer (CIK) cell therapy for patients with hepatocellular carcinoma: efficacy and safety. Exp. Hematol. Oncol., 1(1):11.

[12]Mesiano, G., Todorovic, M., Gammaitoni, L., et al., 2012. Cytokine-induced killer (CIK) cells as feasible and effective adoptive immunotherapy for the treatment of solid tumors. Expert Opin. Biol. Ther., 12(6):673-684.

[13]Morse, M.A., Garst, J., Osada, T., et al., 2005. A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J. Transl. Med., 3(1):9.

[14]Nakano, M., Saeki, C., Takahashi, H., et al., 2012. Activated natural killer T cells producing interferon-gamma elicit promoting activity to murine dendritic cell-based autoimmune hepatic inflammation. Clin. Exp. Immunol., 170(3):274-282.

[15]Olnes, M.J., Erlich, R., 2004. A review and update on cholangiocarcinoma. Oncology, 66(3):167-179.

[16]Pievani, A., Borleri, G., Pende, D., et al., 2011. Dual-functional capability of CD3+CD56+ CIK cells, a T-cell subset that acquires NK function and retains TCR-mediated specific cytotoxicity. Blood, 118(12):3301-3310.

[17]Raposo, G., Nijman, H.W., Stoorvogel, W., et al., 1996. B lymphocytes secrete antigen-presenting vesicles. J. Exp. Med., 183(3):1161-1172.

[18]Schmidt-Wolf, I.G., Lefterova, P., Mehta, B.A., et al., 1993. Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells. Exp. Hematol., 21(13):1673-1679.

[19]Slansky, J.E., Rattis, F.M., Boyd, L.F., et al., 2000. Enhanced antigen-specific antitumor immunity with altered peptide ligands that stabilize the MHC-peptide-TCR complex. Immunity, 13(4):529-538.

[20]Sun, D., Zhuang, X., Zhang, S., et al., 2012. Exosomes are endogenous nanoparticles that can deliver biological information between cells. Adv. Drug. Deliv. Rev., 65(3):342-347.

[21]Taylor, D.D., Gerçel-Taylor, C., Lyons, K.S., et al., 2003. T-cell apoptosis and suppression of T-cell receptor CD3-ζ by Fas ligand containing membrane vesicles shed from ovarian tumors. Clin. Cancer Res., 9(14):5113-5119.

[22]Thompson, C.A., Purushothaman, A., Ramani, V.C., et al., 2013. Heparanase regulates secretion, composition, and function of tumor cell-derived exosomes. J. Biol. Chem., 288(14):10093-10099.

[23]Tschopp, J., Masson, D., Stanley, K.K., 1986. Structural/functional similarity between proteins involved in complement- and cytotoxic T-lymphocyte-mediated cytolysis. Nature, 322(6082):831-834.

[24]Wang, Y., Dai, H., Li, H., et al., 2011. Growth of human colorectal cancer SW1116 cells is inhibited by cytokine-induced killer cells. Clin. Dev. Immunol., 2011:621414.

[25]Welzel, T.M., McGlynn, K.A., Hsing, A.W., et al., 2006. Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States. J. Natl. Cancer Inst., 98(12):873-875.

[26]Wieckowski, E.U., Visus, C., Szajnik, M., et al., 2009. Tumor-derived microvesicles promote regulatory T cell expansion and induce apoptosis in tumor-reactive activated CD8+ T lymphocytes. J. Immunol., 183(6):3720-3730.

[27]Wolfers, J., Lozier, A., Raposo, G., et al., 2001. Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat. Med., 7(3):297-303.

[28]Xue, S.A., Gao, L., Ahmadi, M., et al., 2013. Human MHC class I-restricted high avidity CD4+ T cells generated by co-transfer of TCR and CD8 mediate efficient tumor rejection in vivo. Oncoimmunology, 2(1):e22590.

[29]Yang, Z., Zhang, Q., Xu, K., et al., 2012. Combined therapy with cytokine-induced killer cells and oncolytic adenovirus expressing IL-12 induce enhanced antitumor activity in liver tumor model. PLoS ONE, 7(9):e44802.

[30]Zitvogel, L., Regnault, A., Lozier, A., et al., 1998. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat. Med., 4(5):594-600.

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