Lymphotactin Gene-Modified Bone Marrow Dendritic Cells Act as More Potent Adjuvants for Peptide Delivery to Induce Specific Antitumor Immunity

Abstract

Dendritic cells (DC) are regarded as attractive candidates for cancer immunotherapy. Our aim is to improve the therapeutic efficacy of DC-based tumor vaccine by augmenting DC preferential chemotaxis on T cells. Mouse bone marrow-derived DC were transduced with lymphotactin (Lptn) gene by adenovirus vector. The supernatants from Lptn gene-modified DC (Lptn-DC) were capable of attracting CD4+ and CD8+ T cells in a chemotaxis assay, whereas their mock control could not. Lptn expression of Lptn-DC was further confirmed by RT-PCR. Lptn-DC were pulsed with Mut1 peptide and used for vaccination. Immunization with the low dose (1 × 104) of Mut1 peptide-pulsed DC induced weak CTL activity, whereas the same amounts of Mut1 peptide-pulsed Lptn-DC markedly induced specific CTL against 3LL tumor cells. A single immunization with 1 × 104 Mut1 peptide-pulsed Lptn-DC could render mice resistant to a 5 × 105 3LL tumor cell challenge completely, but their counterpart could not. The protective immunity induced by Mut1 peptide-pulsed Lptn-DC depends on both CD4+ T cells and CD8+ T cells rather than NK cells in the induction phase and depends on CD8+ T cells rather than CD4+ T cells and NK cells in the effector phase. Moreover, the involvement of CD28/CTLA4 costimulation pathway and IFN-γ are also necessary. When 3LL tumor-bearing mice were treated with 1 × 104 Mut1 peptide-pulsed Lptn-DC, their pulmonary metastases were significantly reduced, whereas the same low dose of Mut1 peptide-pulsed DC had no obvious therapeutic effects. Our data suggest that Lptn-DC are more potent adjuvants for peptide delivery to induce protective and therapeutic antitumor immunity.