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

• Published in: PloS one 2012-07, Vol.7 (7), p.e40970-e40970
• Main Authors: Huang, Chiung-Yi, Chen, Jeremy J W, Shen, Kuan-Yin, Chang, Li-Sheng, Yeh, Yi-Chen, Chen, I-Hua, Chong, Pele, Liu, Shih-Jen, Leng, Chih-Hsiang
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Bacteria; Binding sites; Biology; Bone marrow; Bone Marrow Cells - metabolism; Bone Marrow Cells - virology; CD8 antigen; Cell Line; Cervical cancer; Cervix; Cytokines; Cytotoxicity; Dendritic cells; Dendritic Cells - metabolism; Dendritic Cells - virology; Deoxyribonucleic acid; Disease Models, Animal; DNA; Epithelial Cells - cytology; Female; Genes; Health aspects; Helper cells; Human papillomavirus; Humans; Immune response; Immune System; Immunity; Immunity (Disease); Immunization; Immunology; Immunotherapy; Infectious diseases; Lipids; Lipids - chemistry; Lipoproteins; Lymphocytes; Lymphocytes T; Medical research; Medicine; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular biology; Papillomaviridae - metabolism; Papillomavirus E7 Proteins - immunology; Papillomavirus E7 Proteins - metabolism; Papillomavirus infections; Peptides; Polymerase chain reaction; Proteins; Recombinant Proteins - chemistry; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; T cells; T-Lymphocytes; T-Lymphocytes, Cytotoxic - metabolism; T-Lymphocytes, Cytotoxic - virology; Th1 Cells - immunology; Therapeutic applications; TLR2 protein; Toll-like receptors; Tumors; Uterine Cervical Neoplasms - immunology; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - virology; Vaccines; Womens health
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0040970

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.