Treatment with imiquimod enhances antitumor immunity induced by therapeutic HPV DNA vaccination.
BACKGROUND
There is an urgent need to develop new innovative therapies for the control of advanced cancer. The combination of antigen-specific immunotherapy with the employment of immunomodulatory agents has emerged as a potentially plausible approach for the control of advanced cancer.


METHODS
In the current study, we explored the combination of the DNA vaccine encoding calreticulin (CRT) linked to human papillomavirus type 16 (HPV-16) E7 antigen (CRT/E7) with the TLR7 agonist imiquimod for their ability to generate E7-specific immune responses and antitumor effects in tumor-bearing mice.


RESULTS
We observed that treatment with CRT/E7 DNA in combination with imiquimod leads to an enhancement in the E7-specific CD8+ T cell immune responses and a decrease in the number of myeloid-derived suppressor cells in the tumor microenvironment of tumor-bearing mice. Furthermore, treatment with CRT/E7 DNA in combination with imiquimod leads to significantly improved antitumor effects and prolonged survival in treated mice. In addition, treatment with imiquimod led to increased number of NK1.1+ cells and F4/80+ cells in the tumor microenvironment. Macrophages and NK1.1+ cells were found to play an important role in the antitumor effects mediated by treatment with CRT/E7 DNA in combination with imiquimod.


CONCLUSIONS
Thus, our data suggests that the combination of therapeutic HPV DNA vaccination with topical treatment with the TLR7 agonist imiquimod enhances the antitumor immunity induced by DNA vaccination. The current study has significant implications for future clinical translation.
Chuang
Chi-Mu
CM
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Monie
Archana
A
Hung
Chien-Fu
CF
Wu
T-C
TC
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000634:Aminoquinolines / Q000008:administration & dosage*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D037282:Calreticulin / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D052162:Human papillomavirus 16 / Q000235:genetics / Q000276:immunology; D006801:Humans; D000077271:Imiquimod; D007694:Killer Cells, Natural / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008562:Membrane Glycoproteins / Q000819:agonists; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000276:immunology; D053918:Papillomavirus Vaccines / Q000008:administration & dosage* / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics
D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D037282:Calreticulin; D008562:Membrane Glycoproteins; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D019444:Vaccines, DNA; C059731:oncogene protein E7, Human papillomavirus type 16; D000077271:Imiquimod