AAV2/IL-12 gene delivery into dendritic cells (DC) enhances CTL stimulation above other IL-12 applications Evidence for IL-12 intracrine activity in DC

作者：You, Chang-Xuan; Shi, Min; Liu, Yong; Cao, Maohua; Luo, Rongcheng^*; Hermonat, Paul L.

来源：OncoImmunology, 2012, 1(6): 847-855.

DOI：10.4161/onci.20504

• interleukin 12
• intracrine
• dendritic cell
• gene therapy
• adeno-associated virus
• cancer
• cytotoxic T lymphocytes

Adoptive transfer of antigen-specific cytotoxic T lymphocytes (CTL) holds significant promise in treating cancer and Th1 response cytokines are critical for their stimulation. Recently we reported that interleukin 7-(IL-7) and interferongamma-(IFN gamma) autocrine/T cell gene delivery resulted in superior ex vivo CTL stimulation over paracrine/DC delivery. IL-12 is yet another important Th1 cytokine which affects both DC and T cells. Here, using adeno-associated virus Type 2 (AAV2) gene delivery, IL-12-paracrine/DC gene delivery gave significantly superior stimulation of carcinoembryonic antigen (CEA)-specific CTL killing over that induced by autocrine gene delivery (or exogenous IL-12 addition). This is surprising as both AAV2/IL-12-treated T cells and DC secreted approximately the same level of IL-12. Paracrine IL-12 gene delivery also resulted in highest IL-12/IL-10 secretion ratio by DC and highest CD40, CD80, CD83 and CD86 expression. Moreover, AA V2/IL-12-DC stimulated the highest T-cell IFN gamma production, highest T cell proliferation, highest CD69(+)/CD8(+) levels, and lowest level of CD25(+)/CD4(+) Treg. These data strongly suggest that the primary activity of IL-12 during CTL generation is upon the DC. These data are also consistent with there being novel activity for IL-12 within the DC itself, not involving its surface receptor; an "intracrine" activity. Given the plethora of IL-12 studies, these data also suggest that this gene delivery comparison approach could be useful for uncovering new cytokine activities and mechanism(s) of action gone unrecognized by conventional immunologic assays. Finally, these data further suggest AA V2/IL-12 intracrine gene delivery into DC may have utility in immunotherapy protocols involving antigen-specific CTL.

• 出版日期2012-9
• 单位南方医科大学