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Int. J. Mol. Sci. 2014, 15(4), 5508-5521; doi:10.3390/ijms15045508
Article

Transgene IL-6 Enhances DC-Stimulated CTL Responses by Counteracting CD4+25+Foxp3+ Regulatory T Cell Suppression via IL-6-Induced Foxp3 Downregulation

1,2,†
,
1,2,†
,
1,2
,
3
,
4
,
4
,
5
 and
1,2,*
1 Cancer Research Unit, Saskatchewan Cancer Agency, Saskatoon, SK S7N 5E5, Canada 2 Department of Oncology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada 3 Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada 4 Department of Oncology, the First Affiliated Hospital of Soochow University, Soochow 215000, China 5 School of Life Sciences, Beijing Institute of Technology, Beijing 100081, China These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 24 December 2013 / Revised: 25 February 2014 / Accepted: 6 March 2014 / Published: 31 March 2014
(This article belongs to the Special Issue Mechanism of Action and Applications of Cytokines in Immunotherapy)
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Abstract

Dendritic cells (DCs), the most potent antigen-presenting cells have been extensively applied in clinical trials for evaluation of antitumor immunity. However, the efficacy of DC-mediated cancer vaccines is still limited as they are unable to sufficiently break the immune tolerance. In this study, we constructed a recombinant adenoviral vector (AdVIL-6) expressing IL-6, and generated IL-6 transgene-engineered DC vaccine (DCOVA/IL-6) by transfection of murine bone marrow-derived ovalbumin (OVA)-pulsed DCs (DCOVA) with AdVIL-6. We then assessed DCOVA/IL-6-stimulated cytotoxic T-lymphocyte (CTL) responses and antitumor immunity in OVA-specific animal tumor model. We demonstrate that DCOVA/IL-6 vaccine up-regulates expression of DC maturation markers, secretes transgene-encoded IL-6, and more efficiently stimulates OVA-specific CTL responses and therapeutic immunity against OVA-expressing B16 melanoma BL6-10OVA in vivo than the control DCOVA/Null vaccine. Moreover, DCOVA/IL-6-stimulated CTL responses were relatively maintained in mice with transfer of CD4+25+Foxp3+ Tr-cells, but significantly reduced when treated with anti-IL-6 antibody. In addition, we demonstrate that IL-6 down-regulates Foxp3-expression of CD4+25+Foxp3+ Tr-cells in vitro. Taken together, our results demonstrate that AdV-mediated IL-6 transgene-engineered DC vaccine stimulates potent CTL responses and antitumor immunity by counteracting CD4+25+ Tr immunosuppression via IL-6-induced Foxp3 down-regulation. Thus, IL-6 may be a good candidate for engineering DCs for cancer immunotherapy.
Keywords: dendritic cells (DCs); cytotoxic T lymphocytes (CTLs); interleukin-6 (IL-6); forkhead box P3 (Foxp3); antitumor immunity dendritic cells (DCs); cytotoxic T lymphocytes (CTLs); interleukin-6 (IL-6); forkhead box P3 (Foxp3); antitumor immunity
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
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Bhanumathy, K.K.; Zhang, B.; Ahmed, K.A.; Qureshi, M.; Xie, Y.; Tao, M.; Tan, X.; Xiang, J. Transgene IL-6 Enhances DC-Stimulated CTL Responses by Counteracting CD4+25+Foxp3+ Regulatory T Cell Suppression via IL-6-Induced Foxp3 Downregulation. Int. J. Mol. Sci. 2014, 15, 5508-5521.

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