Recombinant lipidated HPV E7 induces a Th-1-biased immune response and protective immunity against cervical cancer in a mouse model

PLoS One. 2012;7(7):e40970. doi: 10.1371/journal.pone.0040970. Epub 2012 Jul 18.

Abstract

The E7 oncoprotein of human papillomavirus (HPV) is an ideal target for developing immunotherapeutic strategies against HPV-associated tumors. However, because protein-based immunogens alone are poor elicitors of the cytotoxic T-lymphocyte (CTL) responses, they have been difficult to exploit for therapeutic purposes. In this study, we report that a recombinant lipoprotein consisting of inactive E7 (E7m) biologically linked to a bacterial lipid moiety (rlipo-E7m) induces the maturation of mouse bone marrow-derived dendritic cells through toll-like receptor 2 (TLR2), skews the immune responses toward the Th1 responses and induces E7-specific CTL responses. We further studied the ability of rlipo-E7m to provide protection against a TC-1 tumor cell challenge in an animal model. Mice prophylactically immunized with two 10-µg doses of rlipo-E7m were found to be free of TC-1 tumor growth. Experiments in a therapeutic immunization model showed that the tumor volume in mice receiving a single dose of rlipo-E7m was less than 0.01 cm(3) on day 40, whereas the tumor volume in mice treated with rE7m was 2.28±1.21 cm(3). The tumor volume of the entire control group was over 3 cm(3). In addition, we demonstrated that the CD8+ T cells play a major role in anti-tumor immunity when administration of rlipo-E7m. These results demonstrate that rlipo-E7m could be a promising candidate for treating HPV-associated tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / virology
  • Cell Line
  • Dendritic Cells / metabolism
  • Dendritic Cells / virology
  • Disease Models, Animal
  • Epithelial Cells / cytology
  • Female
  • Humans
  • Immune System
  • Lipids / chemistry*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Papillomaviridae / metabolism*
  • Papillomavirus E7 Proteins / immunology
  • Papillomavirus E7 Proteins / metabolism*
  • Recombinant Proteins / chemistry
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • T-Lymphocytes
  • T-Lymphocytes, Cytotoxic / metabolism
  • T-Lymphocytes, Cytotoxic / virology
  • Th1 Cells / immunology*
  • Uterine Cervical Neoplasms / immunology*
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / virology

Substances

  • Lipids
  • Papillomavirus E7 Proteins
  • Recombinant Proteins