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

International Journal of Molecular Sciences

Bei Zhang¹  Jim Xiang¹  Kalpana Kalyanasundaram Bhanumathy¹  Khawaja Ashfaque Ahmed¹  Min Tao²  Yufeng Xie²  Mabood Qureshi³  Xin Tan⁴ 

[1] Cancer Research Unit, Saskatchewan Cancer Agency, Saskatoon, SK S7N 5E5, Canada;Department of Oncology, the First Affiliated Hospital of Soochow University, Soochow 215000, China;Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada;School of Life Sciences, Beijing Institute of Technology, Beijing 100081, China;

关键词: dendritic cells (DCs);    cytotoxic T lymphocytes (CTLs);    interleukin-6 (IL-6);    forkhead box P3 (Foxp3);    antitumor immunity;   

DOI  :  10.3390/ijms15045508

来源: DOAJ

【 摘 要 】

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-6down-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.

【 授权许可】

Unknown