title: Enhancement of CD4+ T-cell help reverses the doxorubicin-induced suppression of antigen-specific immune responses in vaccinated mice.
abstract: 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.
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: D
authors.initials: D
authors.lastname: Kim
authors.forename: A
authors.initials: A
authors.lastname: Monie
authors.forename: Y-C
authors.initials: YC
authors.lastname: Tsai
authors.forename: L
authors.initials: L
authors.lastname: He
authors.forename: M-C
authors.initials: MC
authors.lastname: Wang
authors.forename: C-F
authors.initials: CF
authors.lastname: Hung
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D019470:Biolistics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D037282:Calreticulin / Q000235:genetics; D019496:Cancer Vaccines / Q000008:administration & dosage*; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000276:immunology; D004317:Doxorubicin / Q000627:therapeutic use*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016233:Immunotherapy, Active / Q000379:methods*; D008213:Lymphocyte Activation; D017780:Malaria Vaccines / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D009856:Oncogene Proteins, Viral / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D037282:Calreticulin; D019496:Cancer Vaccines; C466080:E6 protein, human papillomavirus type 1; D007166:Immunosuppressive Agents; D017780:Malaria Vaccines; D009856:Oncogene Proteins, Viral; C401223:PADRE 45; D004317:Doxorubicin