Heterologous vaccination targeting prostatic acid phosphatase (PAP) using DNA and Listeria vaccines elicits superior anti-tumor immunity dependent on CD4+ T cells elicited by DNA priming

摘要

Background. Sipuleucel T, an autologous cell-based vaccine targeting prostatic acid phosphatase (PAP), has demonstrated efficacy for the treatment of advanced prostate cancer. DNA vaccines encoding PAP and live attenuated Listeria vaccines have entered clinical trials for patients with prostate cancer, and have advantages in terms of eliciting predominantly Th1-biased immunity. In this study, we investigated whether the immunogenicity and anti-tumor efficacy of a DNA and Listeria vaccine, each encoding PAP, could be enhanced by using them in a heterologous prime/boost approach. Methods. Transgenic mice expressing HLA-A2.01 and HLA-DRB1*0101 were immunized alone or with a heterologous prime/boost strategy. Splenocytes were evaluated for MHC class I and ll-restricted, PAP-specific immune responses by IFNγ ELISPOTs. Anti-tumor activity to a syngeneic, PAP-expressing tumor line was evaluated. Results. PAP-specific cellular immunity and anti-tumor activity were elicited in mice after immunization with DNA- or listeria-based vaccines. Greater CD4+ and CD8+ responses, and anti-tumor responses, were elicited when mice were immunized first with DNA and boosted with Listeria, but not when administered in the opposite order. This was found to be dependent on CD4+ T cells elicited with DNA priming, and was not due to inflammatory signals by Listeria itself or due to B cells serving as antigen-presenting cells for DNA during priming. Conclusions. Heterologous prime/boost vaccination using DNA priming with Listeria boosting may provide better anti-tumor immunity, similar to many reports evaluating DNA priming with vaccines targeting foreign microbial antigens. These findings have implications for the design of future clinical trials.