title: Transgene IL-6 enhances DC-stimulated CTL responses by counteracting CD4+25+Foxp3+ regulatory T cell suppression via IL-6-induced Foxp3 downregulation.
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.
authors.affiliation: Cancer Research Unit, Saskatchewan Cancer Agency, Saskatoon, SK S7N 5E5, Canada. kak677@mail.usask.ca.
authors.forename: Kalpana Kalyanasundaram
authors.initials: KK
authors.lastname: Bhanumathy
authors.affiliation: Cancer Research Unit, Saskatchewan Cancer Agency, Saskatoon, SK S7N 5E5, Canada. bei.zhang@usask.ca.
authors.forename: Bei
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Cancer Research Unit, Saskatchewan Cancer Agency, Saskatoon, SK S7N 5E5, Canada. kaa201@mail.usask.ca.
authors.forename: Khawaja Ashfaque
authors.initials: KA
authors.lastname: Ahmed
authors.affiliation: Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada. mabood.qureshi@saskatoonhealthregion.ca.
authors.forename: Mabood
authors.initials: M
authors.lastname: Qureshi
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Soochow University, Soochow 215000, China. sdxyf@163.com.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Soochow University, Soochow 215000, China. mtao@medmail.com.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Tao
authors.affiliation: School of Life Sciences, Beijing Institute of Technology, Beijing 100081, China. tanxing@bit.edu.cn.
authors.forename: Xin
authors.initials: X
authors.lastname: Tan
authors.affiliation: Cancer Research Unit, Saskatchewan Cancer Agency, Saskatoon, SK S7N 5E5, Canada. jim.xiang@usask.ca.
authors.forename: Jim
authors.initials: J
authors.lastname: Xiang
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015704:CD4 Antigens / Q000276:immunology; D019496:Cancer Vaccines / Q000138:chemical synthesis / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D003713:Dendritic Cells / Q000276:immunology*; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014162:Transfection / Q000379:methods; D014611:Vaccination; D014614:Vaccines, Synthetic
chemical_list: D015704:CD4 Antigens; D019496:Cancer Vaccines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D014614:Vaccines, Synthetic; D010047:Ovalbumin