eISSN: 1644-4124
ISSN: 1426-3912
Central European Journal of Immunology
Current issue Archive Manuscripts accepted About the journal Abstracting and indexing Subscription Contact Instructions for authors
SCImago Journal & Country Rank

2/2018
vol. 43
 
Share:
Share:
more
 
 
abstract:
Experimental immunology

Neutralizing TGF-β promotes anti-tumor immunity of dendritic cells against pancreatic cancer by regulating T lymphocytes

Ning Pu, Guochao Zhao, Shanshan Gao, Yutong Cui, Yadong Xu, Yang Lv, Abulimiti Nuerxiati, Wenchuan Wu

(Centr Eur J Immunol 2018; 43 (2): 123-131)
Online publish date: 2018/06/30
View full text
Get citation
ENW
EndNote
BIB
JabRef, Mendeley
RIS
Papers, Reference Manager, RefWorks, Zotero
AMA
APA
Chicago
Harvard
MLA
Vancouver
 
Previous fundamental or clinical trials of dendritic cell (DC) vaccine against pancreatic ductal adeno­carcinoma (PDAC) revealed the burgeoning neoadjuvant immunotherapy. Microarray studies indicated that multiple ingredients of the transfer growth factor beta (TGF-) pathway were over­expressed in PDAC, which inhibited the intratumoral immune response. To explore whether the DC volume in tumor microenvironment contributes to the differentiation of T cell cohort and test the hypo­thesis that combining DC vaccine with TGF- inhibitors will elevate the anti-tumor immune response, we managed to co-culture T cells in vitro with pancreatic cancer cells and DCs in different concentrations, and combine TGF- blockage with DC vaccine therapy in a murine model of pancreatic cancer. In in vitro studies, we discovered that CD8+ T cytotoxic cell (Tc) presented a significant advantage and lower volume of CD4+ T helper cell (Th) existed with a certain elevated DC concentration (p < 0.05), associated with declined interleukin (IL)-10 and increased interferon (IFN)-, which suggested with the DC volume increasing, the enhancing immune effect may represent a great advantage in such a system (p < 0.05). When interfered with anti-TGF- antibody or TGF- cytokine, respectively, in the co-culture system, we found IFN- producing was extremely higher and T cell apoptosis relatively descent with TGF- blockage (p < 0.05). The murine PDAC model demonstrated a survival advantage treated with anti-TGF- antibody combined with DC vaccine when compared with monotherapy controls (p < 0.05). Therefore, these findings indicated that, through neutralizing TGF- associated with DC vaccine, the anti-tumor immunity is highly elevated and this combinational therapy will provide an efficacious prospect.
keywords:

pancreatic ductal adenocarcinoma, DCs, TGF-beta, immunotherapy, prognosis

references:
Martin RC 2nd, McFarland K, Ellis S, et al. (2012): Irreversible electroporation therapy in the management of locally advanced pancreatic adenocarcinoma. J Am Coll Surg 215: 361-369.
Thanos L, Poulou LS, Mailli L, et al. (2010): Image-guided radiofrequency ablation of a pancreatic tumor with a new triple spiral-shaped electrode. Cardiovasc Intervent Radiol 33: 215-218.
Carrafiello G, Ierardi AM, Fontana F, et al. (2013): Microwave ablation of pancreatic head cancer: safety and efficacy. J Vasc Interv Radiol 24: 1513-1520.
Casadei R, Ricci C, Pezzilli R, et al. (2010): A prospective study on radiofrequency ablation locally advanced pancreatic cancer. Hepatobiliary Pancreat Dis Int 9: 306-311.
Carrafiello G, Ierardi AM, Piacentino F, et al. (2012): Microwave ablation with percutaneous approach for the treatment of pancreatic adenocarcinoma. Cardiovasc Intervent Radiol 35: 439-442.
Siegel RL, Miller KD, Jemal A (2016): Cancer statistics, 2016. CA Cancer J Clin 66: 7-30.
Ino Y, Yamazaki-Itoh R, Shimada K, et al. (2013): Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br J Cancer 108: 914-923.
Protti MP, De Monte L (2013): Immune infiltrates as predictive markers of survival in pancreatic cancer patients. Front Physiol 4: 210.
Kotteas E, Saif MW, Syrigos K (2016): Immunotherapy for pancreatic cancer. J Cancer Res Clin Oncol 142: 1795-1805.
Liu L, Zhao G, Wu W, et al. (2016): Low intratumoral regulatory T cells and high peritumoral CD8(+) T cells relate to long-term survival in patients with pancreatic ductal adenocarcinoma after pancreatectomy. Cancer Immunol Immunother 65: 73-82.
Tang Y, Xu X, Guo S, et al. (2014): An increased abundance of tumor-infiltrating regulatory T cells is correlated with the progression and prognosis of pancreatic ductal adenocarcinoma. PLoS One 9: e91551.
Chen X, Du Y, Huang Z (2012): CD4+CD25+ Treg derived from hepatocellular carcinoma mice inhibits tumor immunity. Immunol Lett 148: 83-89.
Ikushima H, Miyazono K (2010): TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer 10: 415-424.
Ijichi H. (2004): TGF-beta signaling pathway in pancreatic cancer cells. Nihon Rinsho 62: 1241-1248.
Inaba K, Inaba M, Romani N, et al. (1992): Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony- stimulating factor. J Exp Med 176: 1693-1702.
Kosmaczewska A, Ciszak L, Potoczek S, et al. (2008): The significance of Treg cells in defective tumor immunity. Arch Immunol Ther Exp (Warsz) 56: 181-191.
Khazaie K, von Boehmer H (2006): The impact of CD4+CD25+ Treg on tumor specific CD8+ T cell cytotoxicity and cancer. Semin Cancer Biol 16: 124-136.
Yamamoto T, Yanagimoto H, Satoi S, et al. (2012): Circulating CD4+CD25+ regulatory T cells in patients with pancreatic cancer. Pancreas 41: 409-415.
Xiang ST, Zhou SW, Guan W, et al. (2005): Expression of MUC1 and distribution of tumor-infiltrating dentritic cells in human bladder transitional cell carcinoma. Di Yi Jun Yi Da Xue Xue Bao 25: 1114-1118.
Soruri A, Fayyazi A, Neumann C, et al. (2001): Ex vivo generation of human anti-melanoma autologous cytolytic T cells by dentritic cell/melanoma cell hybridomas. Cancer Immunol Immunother 50: 307-314.
Bhairavabhotla RK, Verm V, Tongaonkar H, et al. (2007): Role of IL-10 in immune suppression in cervical cancer. Indian J Biochem Biophys 44: 350-356.
Kindlund B, Sjoling A, Yakkala C, et al. (2017): CD4+ regulatory T cells in gastric cancer mucosa are proliferating and express high levels of IL-10 but little TGF-beta. Gastric Cancer 20: 116-125.
Fullerton PT Jr., Creighton CJ, Matzuk MM (2015): Insights Into SMAD4 Loss in Pancreatic Cancer From Inducible Restoration of TGF-beta Signaling. Mol Endocrinol 29: 1440-1453.
Truty MJ, Urrutia R (2007): Basics of TGF-beta and pancreatic cancer. Pancreatology 7: 423-435.
Javle M, Li Y, Tan D, et al. (2014): Biomarkers of TGF-beta signaling pathway and prognosis of pancreatic cancer. PLoS One 9: e85942.
Soares KC, Rucki AA, Kim V, et al. (2015): TGF-beta blockade depletes T regulatory cells from metastatic pancreatic tumors in a vaccine dependent manner. Oncotarget 6: 43005-43015.
Greco SH, Tomkotter L, Vahle AK, et al. (2015): TGF-beta Blockade Reduces Mortality and Metabolic Changes in a Validated Murine Model of Pancreatic Cancer Cachexia. PLoS One 10: e0132786.
FEATURED PRODUCTS
Quick links
© 2018 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.
PayU - płatności internetowe