Enhancement of Immunotherapeutic Effects of HPV16E7 on Cervical Cancer by Fusion with CTLA4 Extracellular Region

Yi Zheng; Yijuan Zhang; Jun Wan; Chaofan Shi; Laiqiang Huang

doi:10.1007/s12275-008-0087-1

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Research Support, Non-U.S. Gov't
Enhancement of Immunotherapeutic Effects of HPV16E7 on Cervical Cancer by Fusion with CTLA4 Extracellular Region: Yi Zheng , Yijuan Zhang , Jun Wan , Chaofan Shi , Laiqiang Huang; Journal of Microbiology 2008;46(6):728-736.
DOI: https://doi.org/10.1007/s12275-008-0087-1
Published online: December 24, 2008

The Shenzhen Key Lab of Gene and Antibody Therapy, Center for Biotech and BioMedicine and Division of Life Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen, Guangdong 518055, P. R. ChinaThe Shenzhen Key Lab of Gene and Antibody Therapy, Center for Biotech and BioMedicine and Division of Life Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen, Guangdong 518055, P. R. China

Corresponding author: Laiqiang Huang , Tel: 86-755-2603-6052,

Received: 8 April 2008 • Accepted: 23 September 2008

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Abstract

Cervical cancer is caused by infection by high-risk human papillomavirus (HPV), especially HPV16. Limitations in current treatments of cervical cancers call for the development of new and improved immunotherapies. This study aims at investigating the efficacy of a novel vaccine consisting of modified HPV 16E7 fused with human cytotoxic T-lymphocyte antigen 4 (CTLA4). The regions in HPV16 E7 gene associated with its transformation and CTL-enhanced response were modified; the resultant HPV16mE7 was fused with extracellular region of CTLA4 to generate HPVm16E7-eCTLA4 fusion protein. Binding of this fusion protein to B7 molecules expressed on antigen presenting-cells (APCs) was demonstrated. C57BL/6 (H-2b) mice immunized with low dose of the fusion protein (10 μg) produced higher titer antibody and stronger specific CTL response, and expressed higher levels of IFN-γ and IL-12, compared with those immunized with HPVm16E7 only or admixture of HPVm16E7 and CTLA4, or PBS; and were protected from lethal dose tumor challenge. Tumor growth was retarded and survival prolonged in mouse models with the fusion protein treatment. Our results demonstrate that fusion of HPV16 E7 with eCTLA4 targeting APCs resulted in enhanced immunity, and that this fusion protein may be useful for improving the efficacy of immunotherapeutic treatments of cervical cancer and other HPV16 infection-associated tumors.

Keywords: cervical cancer;human papillomavirus 16 (HPV16);cytotoxic T-lymphocyte antigen 4 (CTLA4)

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Enhancement of Immunotherapeutic Effects of HPV16E7 on Cervical Cancer by Fusion with CTLA4 Extracellular Region

J. Microbiol. 2008;46(6):728-736. Published online December 24, 2008

DOI: https://doi.org/10.1007/s12275-008-0087-1

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