Immunological Protection against HPV16 E7-Expressing Human Esophageal Cancer Cell Challenge by a Novel HPV16-E6/E7 Fusion Protein Based-Vaccine in a Hu-PBL-SCID Mouse Model

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  • Lu Yuanzhi
    Laboratory of Cellular and Molecular Biology, Cancer Institute & Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences
  • Zhang Zhixin
    Beijing Blood Center
  • Liu Qiao
    Laboratory of Cellular and Molecular Biology, Cancer Institute & Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences
  • Liu Bo
    Laboratory of Cellular and Molecular Biology, Cancer Institute & Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences
  • Song Xinxin
    Laboratory of Cellular and Molecular Biology, Cancer Institute & Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences
  • Wang Mingrong
    State Key Laboratory of Molecular Oncology, Cancer Institute & Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences
  • Zhao Xinhua
    Laboratory of Cellular and Molecular Biology, Cancer Institute & Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences
  • Zhao Qingzheng
    Laboratory of Cellular and Molecular Biology, Cancer Institute & Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences

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Abstract

Increasing evidence has suggested that infection with high-risk human papillomavirus (HPVs) is closely associated with esophageal squamous cell carcinoma (ESCC) in China. The E6 and E7 oncoproteins expressed in ESCC are considered as attractive tumor-specific antigen targets for immunotherapy. We have reported that the HPV16 mE6Δ/mE7/TBhsp70Δ fusion protein vaccination induced powerful anti-tumor immunity against TC-1 tumor cells in a C57BL/6 mouse model. In the present study, we further evaluate the protective efficacy of this fusion protein vaccine using an HPV E7-expressing human ESCC cell line (EC9706) and a Hu-PBL-SCID mouse model. We demonstrated that immunization with the fusion protein vaccine caused significant inhibition of tumor growth with the delay time to tumor detection (tests vs. controls, 16 d vs. 9 d, p<0.01) and much smaller tumor size (p<0.01) in vivo. The inhibitory rate was ca. 69.6%, and 25% of the fusion protein vaccinated-mice remained tumor free by the end of the experiment (42 d). Furthermore, the activated lymphocytes (CD8+) were capable of infiltrating into the tumor site, and much more apoptotic cells along with activation of caspase-3 were observed in the tumors from vaccinated-mice. Also, high expression levels of human IFN-γ, TNF-α, granzyme B and perforin were detected in the tumors from vaccinated-mice. Therefore, we concluded that the HPV16 mE6Δ/mE7/TBhsp70Δ fusion protein vaccine is able to stimulate cellular-mediated immune response against E7-containing ESCC cells through CD8+-dependent CTL-induced apoptosis in Hu-PBL-SCID mice. These findings provide a scientific basis for HPV E7-expressing ESCC active immunotherapy.

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