Prophylactic, therapeutic and anti-metastatic effects of an HPV-16mE6Delta/mE7/TBhsp70Delta fusion protein vaccine in an animal model.
Human papillomaviruses (HPVs), particularly HPV-16, are not only causally linked to cervical cancers but also play an important role in the development of other cancers. The oncoproteins, E6 and E7, are consistently coexpressed in the majority of HPV-containing carcinomas and their metastatic lesions, and are critical to the induction and maintenance of malignant phenotype, and also can cause tumor metastasis. Therefore, E6 and E7 represent ideal tumor-specific antigens for the development of immunotherapy to prevent and treat HPV-associated cancers and their metastases. The powerful antigenic nature of Mycobacterium tuberculosis heat shock protein 70 (TBhsp70) is emphasized by evidence that mammals are capable of recognizing murine and human multiple B and T cell epitopes in this protein, and therefore allows it to be used as an adjuvant-free carrier to stimulate the immune response to a covalently linked fusion partner. In our present study, we developed a recombinant TBhsp70Delta protein expression vector that permits the production of other protein fused to TBhsp70Delta. A recombinant HPV-16mE6Delta/mE7/TBhsp70Delta fusion protein was expressed and purified, and immunization with the fusion protein in the absence of adjuvant was capable of providing strong protection to C57BL/6 mice against challenge and rechallenge with TC-1 cells, but not HPV negative Lewis lung cancer cells, and induced established TC-1 tumor regression and led to long-term survival. Consistent with the in vivo results, the fusion protein immunization in the absence of adjuvant induced cytolytic T lymphocytes recognized specifically TC-1 tumor cells in vitro. We also demonstrated that immunization with the fusion protein in the absence of adjuvant was effective in both preventing and treating TC-1 metastatic lesions in the lung metastasis model. In particular, immunization with the fusion protein caused regression of established lung metastatic lesions in 50% of immunized animals. This study represents an instance of tumor therapy with a TBhsp70Delta fusion protein and provides the scientific basis for the clinical application of the HPV16mE6Delta/mE7/TBhsp70Delta fusion protein in the treatment of HPV-associated cancers and their metastases.
Qian
Xinlai
X
Department of Cellular and Molecular Biology, Cancer Institute & Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100021, PR China.
Lu
Yuanzhi
Y
Liu
Qiao
Q
Chen
Ke
K
Zhao
Qingzheng
Q
Song
Jietao
J
D000818:Animals; D001426:Bacterial Proteins / Q000276:immunology*; D002461:Cell Line, Transformed; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology*; D052162:Human papillomavirus 16; D016233:Immunotherapy, Active; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009368:Neoplasm Transplantation; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000627:therapeutic use; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000517:prevention & control*; D014765:Viral Vaccines / Q000627:therapeutic use*
D001426:Bacterial Proteins; C068651:E6 protein, Human papillomavirus type 16; D018840:HSP70 Heat-Shock Proteins; C444642:HSP70 protein, Mycobacterium tuberculosis; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014765:Viral Vaccines; C059731:oncogene protein E7, Human papillomavirus type 16