Murine dendritic cells transfected with human gp100 elicit both antigen-specific CD8(+) and CD4(+) T-cell responses and are more effective than DNA vaccines at generating anti-tumor immunity

Dendritic cells (DCs) are potent inducers of cytotoxic T lymphocytes (CTLs) when pulsed with an antigenic peptide or tumor lysate, In this report, we have used liposome-mediated gene transfer to examine the ability of plasmid DNA encoding the human melanoma-associated antigen gp100 to elicit CD8(+) and CD4(+) T-cell responses. We also compared the efficacy between gp100 ge ne-modified DCs and naked DNA (pCDNA3/gp100)-based vaccines at inducing ant i-tumor immunity. DCs were generated from murine bone marrow and transfecte d in vitro with plasmid DNA containing the gp100 gene. These gp100-modified DCs (DC/gps) were used to stimulate syngeneic naive spleen T cells in vitr o or to immunize mice in vivo. Antigen-specific, MHC-restricted CTLs were g enerated when DC/gps were used to prime T cells both in vitro and in vivo. Thus, these CTLs were cytolytic for gp100-transfected syngeneic (H-2(b)) tu mor MCA106 (MCA/gp) and vaccinia-pMel17/gp100-infected syngeneic B16 and MC A106, but not parental tumor MCA106 and B16, or gp100-transfected allogenei c tumor P815 (H-2(d)). Immunization with DC/gp protected mice from subseque nt challenge with MCA/gp but not parental MCA106, Antibody-mediated T-cell subset depletion experiments demonstrate that induction of CTLs in vivo is dependent on both CD4(+) and CD8(+) T cells. Furthermore, DC/gp immunizatio n elicits an antigen-specific CD4(+) T-cell response, suggesting that DC/gp s present MHC class II epitopes to CD4(+) T cells. In addition, our data sh ow that gene-modified, DC-based vaccines are more effective than the naked DNA-based vaccines at eliciting anti-tumor immunity in both prophylactic an d therapeutic models. These results suggest that the use of DCs transfected with plasmid DNA containing a gene for TAA may be superior to peptide-puls ed DCs and naked DNA-based vaccines for immunotherapy and could provide an alternative strategy for tumor vaccine design. Int. J. Cancer 83:532-540, 1 999. (C) 1999 Wiley-Liss, Inc.