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.
Highlights
Immune surveillance by CD8+ cytotoxic T lymphocytes (CTLs) represents a major mechanism for the detection and elimination of pathogen-infected cells
To assess the transcriptional IL-6 expression, RNA extracted from AdVIL-6 was subjected to reverse transcription-polymerase chain reaction (RT-PCR) analysis using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as the loading control
We demonstrated that DCOVA expressed Dendritic cells (DCs) marker CD11c, adhesion molecule CD54 and DC maturation markers CD40, CD80 and Iab (Figure 1C), and secreted little amount of IL-6 (0.03 ng/mL)
Summary
Immune surveillance by CD8+ cytotoxic T lymphocytes (CTLs) represents a major mechanism for the detection and elimination of pathogen-infected cells. In general, the efficacy of DC-mediated cancer vaccine is still limited, mostly because DC vaccines are unable to sufficiently break the suppressive tumor microenvironment and immune tolerance in cancer patients [4] Inflammatory cytokines such as IL-2, IL-6, IL-12, IL-15 and TNF-α play an important role in inflammation, innate and adaptive immunity [7]. To improve the efficacy of DC vaccine, DCs were genetically modified to produce IL-2 or IL-12 [8,9] These engineered DC vaccines induced potent antitumor immunity via activation of strong CTL responses. We previously demonstrated that inflammatory cytokine TNF-α transgene-expressing DCs underwent augmented cellular maturation and induced more robust CTL responses and antitumor immunity [11]. DCs (DCOVA) with AdVIL-6 and further assessed DCOVA/IL-6-stimulated CTL responses and antitumor immunity in an OVA-specific animal tumor model.
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