Enhancement of CD4+ T-cell help reverses the doxorubicin-induced suppression of antigen-specific immune responses in vaccinated mice

Multimodality treatments that combine conventional cancer therapies with antigen-specific immunotherapy have emerged as promising approaches for the control of cancer. In the current study, we have explored the effect of doxorubicin on the antigen-specific immune responses generated in mice vaccinated with calreticulin (CRT)/E6 and/or Ii-PADRE DNA. We observed that pretreatment with doxorubicin suppressed the E6-specific CD8+ T-cell immune responses generated by CRT/E6 DNA vaccination in vaccinated mice. In contrast, pretreatment with doxorubicin enhanced the PADRE-specific CD4+ T-cell immune responses generated by Ii-PADRE DNA vaccination. Furthermore, coadministration of Ii-PADRE DNA could not only reverse the suppression, but also enhanced the E6-specific CD8+ T-cell responses in CRT/E6-vaccinated mice pretreated with doxorubicin. Finally, treatment with doxorubicin followed by CRT/E6 combined with Ii-PADRE DNA vaccination led to enhanced antitumor effects and prolonged survival in TC-1 tumor-bearing mice. The clinical implications of the current study are discussed.