Premium
Eradication of large tumors expressing human papillomavirus E7 protein by therapeutic vaccination with E7 fused to the extra domain a from fibronectin
Author(s) -
Mansilla Cristina,
Berraondo Pedro,
Durantez Maika,
Martínez Marta,
Casares Noelia,
Arribillaga Laura,
Rudilla Francesc,
Fioravanti Jessica,
Lozano Teresa,
Villanueva Lorea,
Sarobe Pablo,
Borrás Francisco,
Leclerc Claude,
Prieto Jesús,
Lasarte Juan José
Publication year - 2011
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.26412
Subject(s) - cancer research , fusion protein , tlr2 , medicine , cd8 , tlr9 , immunology , immune system , biology , innate immune system , recombinant dna , biochemistry , gene expression , dna methylation , gene
Cervical carcinoma is one of the most common cancers in women worldwide. It is well established that chronic infection of the genital tract by various mucosatropic human papillomavirus (HPV) types causes cervical cancer. Cellular immunity to E7 protein from HPV (HPVE7) has been associated with clinical and cytologic resolution of HPV‐induced lesions. Thus, we decided to test if targeting of HPVE7 to dendritic cells using a fusion protein containing the extra domain A (EDA) from fibronectin, a natural ligand for TLR4, and HPVE7 (EDA‐HPVE7) might be an efficient vaccine for the treatment of cervical carcinoma. We found that EDA‐HPVE7 fusion protein was efficiently captured by bone marrow derived dendritic cells in vitro and induced their maturation, with the upregulation of maturation markers and the production of IL‐12. Immunization of mice with EDA‐HPVE7 fusion protein induced antitumor CD8 + T cell responses in the absence of additional adjuvants. Repeated intratumoral administration of EDA‐HPVE7 in saline was able to cure established TC‐1 tumors of 5–7 mm in diameter. More importantly, intravenous injection with EDA‐HPVE7 in combination with the TLR ligand polyinosinic‐polycytidylic acid (pIC), or with low doses of cyclophosphamide and the TLR9 ligand CpG‐B complexed in cationic lipids, were able to eradicate large established TC‐1 tumors (1.2 cm in diameter). Thus, therapeutic vaccination with EDA‐HPVE7 fusion protein may be effective in the treatment of human cervical carcinoma.