Silencing Ido2 In Dendritic Cells: A Novel Strategy To Strengthen Cancer Immunotherapy In A Murine Lung Cancer Model

While dendritic cell (DC)-based immunotherapy has achieved satisfactory results in animal models, its effects were not satisfactory as initially expected in clinical applications, despite the safety and varying degrees of effectiveness in various types of cancer. Improving the efficacy of the DC-based vaccine is essential for cancer immunotherapy. The present study aimed to investigate methods with which to amplify and enhance the antitumor immune response of a DC-based tumor vaccine by silencing the expression of indoleamine 2,3-dioxygenase 2 (IDO2), a tryptophan rate-limiting metabolic enzyme in DCs. In vitro experiments revealed that the silencing of IDO2 in DCs did not affect the differentiation of DCs, whereas it increased their expression of costimulatory molecules following stimulation with tumor necrosis factor (TNF)-alpha and tumor lysate from Lewis lung cancer (LLC) cells. In a mixed co-culture system, the IDO2-silenced DCs promoted the proliferation of T-cells and reduced the induction of regulatory T-cells (Tregs). Further in vivo experiments revealed that the silencing of IDO2 in DCs markedly suppressed the growth of tumor cells. Moreover, treatment with the IDO2-silenced DC-based cancer vaccine enhanced cytotoxic T lymphocyte activity, whereas it decreased T-cell apoptosis and the percentage of CD4(+)CD25(+)Foxp3(+)Tregs. On the whole, the present study provides evidence that the silencing of the tryptophan rate-limiting metabolic enzyme, IDO2, has the potential to enhance the efficacy of DC-based cancer immunotherapy.