Induction of antitumor immunity ex vivo using dendritic cells transduced with fowl pox vector expressing MUC1, CEA, and a triad of costimulatory molecules (rF-PANVAC)

The fowl pox vector expressing the tumor associated antigens MUC1 and CEA in the context of costimulatory molecules (rF-PANVAC) has shown promise as a tumor vaccine. However, vaccine mediated expansion of suppressor T cell populations may blunt clinical efficacy. We characterized the cellular immune response induced by ex-vivo dendritic cells (DCs) transduced with (rF)-PANVAC. Consistent with the functional characteristics of potent antigen presenting cells, rF-PANVAC-DCs demonstrated strong expression of MUC1 and CEA and costimulatory molecules, CD80, CD86, and CD83; decreased levels of phosphorylated STAT3, and increased levels of Tyk2, JAK2 and STAT1. rF-PANVAC-DCs stimulated expansion of tumor antigen specific T cells with potent cytolytic capacity. However, rF-PANVAC transduced DCs also induced the concurrent expansion of FOXP3 expressing CD4+CD25+high regulatory T cells (Tregs) that inhibited T cell activation. Moreover, Tregs expressed high levels of Th2 cytokines (IL-10, IL-4, IL-5, and IL-13) together with phosphorylated STAT3 and STAT6. In contrast, the vaccine expanded Treg population expressed high levels of Th1 cytokines IL-2 and IFNγ and the proinflammatory RORγt and IL-17A suggesting that these cells may share effector functions with conventional TH17 T cells. These data suggest that Tregs expanded by rF-PANVAC-DCs, exhibit immunosuppressive properties potentially mediated by Th2 cytokines, but simultaneous expression of Th1 and Th17 associated factors suggests a high degree of plasticity.