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Cancer vaccines seek to harness the specificity of T and B lymphocytes for reduction of tumor burden, as well as prevention of recurrent disease by establishing immunological memory. Because of their ability to initiate adaptive immune responses, dendritic cells (DCs) presenting tumor antigens have frequently been used as cancer vaccines. Unfortunately, induction of therapeutic responses in cancer patients has been sporadic, suggesting that current DC vaccines are unable to surmount tolerance against tumor antigens. The transduction of DCs with recombinant viral vectors may be a viable strategy for augmenting the ability of DC vaccines to break tolerance, as this approach can be used to efficiently deliver tumor antigens to DCs in the context of an immunostimulatory viral infection. Therefore, we have investigated the potential of DCs transduced with Venezuelan equine encephalitis virus replicon particles (VRPs) as cancer vaccines. VRPs could efficiently transduce human and murine immature DCs ex vivo, leading to high-level transgene expression, DC maturation, secretion of proinflammatory cytokines and efficient presentation of VRP-encoded antigens to T cells. VRP-transduced DCs (VRP-DCs) expressing a truncated neu oncoprotein stimulated neu-specific T cell and antibody responses and induced regression of established tumors in nontolerant mice. In contrast, VRP-DCs failed to induce robust antitumor responses in mice tolerant to neu, and were likewise unable to inhibit tumor growth. Depletion of CD4+CD25+ regulatory T cells (Treg) improved the effectiveness of VRP-DC vaccines in tolerant mice, demonstrating that VRP-DCs alone were unable to overcome Treg activity. Furthermore, provision of tolerant mice with neu-specific T cells from nontolerant mice did not augment vaccine efficacy, indicating that tolerogenic mechanisms are dominant over effector T cell activity. These results demonstrate that while highly immunogenic, virally-activated DCs cannot break tolerance against self/tumor antigens. Moreover, these findings imply that potent DC vaccines alone are unlikely to induce therapeutic antitumor immunity unless additional measures are undertaken to inhibit immunoregulatory mechanisms.