Immunisation with modified HPV16 E7 genes against mouse oncogenic TC-1 cell sublines with downregulated expression of MHC class I molecules

Vaccine. 2003 Mar 7;21(11-12):1125-36. doi: 10.1016/s0264-410x(02)00519-4.

Abstract

Human papillomavirus type 16 (HPV16)-transformed mouse TC-1 cells are extensively used in the evaluation of efficacy of experimental vaccines against tumours induced by HPVs. As these cells strongly express MHC class I molecules and downregulation of MHC class I surface expression is one of the important mechanisms that enable tumour escape from the host immune system, we undertook to derive TC-1 clones with reduced expression of MHC class I antigens. TC-1 cells were inoculated into mice preimmunised with an E7 gene-based DNA vaccine and from tumours developing in a portion of the animals, cell clones with downregulated MHC class I surface expression were isolated. Treatment with IFN-gamma resulted in an upregulation of MHC class I molecules in these cells, but after IFN-gamma removal, their expression gradually dropped again. When the expression of some components of the antigen-processing machinery (APM; LMP-2, TAP-1, and TAP-2) was tested, a reduced TAP-1 production was detected in cell lines with downregulated MHC class I expression. An enhanced immunoresistance of TC-1-derived clones with reduced MHC class I expression was observed in animals immunised with plasmids carrying modified E7 genes. Apart from the previously described fusion gene Sig/E7/LAMP-1, a new construct, Sig/E7GGG/LAMP-1, with a mutated Rb-binding site, was also used for immunisation. No significant change of immunogenicity was recorded for Sig/E7GGG/LAMP-1. Cell lines with downregulated MHC class I expression derived from TC-1 cells may represent a useful model for testing therapeutic anti-HPV vaccines in settings more relevant to clinical requirements.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation / genetics
  • Antigens, Neoplasm / biosynthesis
  • Antigens, Neoplasm / immunology*
  • Biolistics
  • Cancer Vaccines / immunology
  • Cancer Vaccines / therapeutic use*
  • Cell Line, Transformed / immunology
  • Cell Line, Transformed / transplantation
  • Cell Transformation, Viral
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genes, MHC Class I
  • Genes, Synthetic
  • Genes, ras
  • H-2 Antigens / biosynthesis
  • H-2 Antigens / genetics
  • H-2 Antigens / immunology*
  • Immunization
  • Immunotherapy, Active*
  • Interferon-gamma / pharmacology
  • Lung
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Transplantation
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / prevention & control*
  • Oncogene Proteins, Viral / genetics
  • Oncogene Proteins, Viral / immunology*
  • Oncogene Proteins, Viral / physiology
  • Papillomaviridae / genetics
  • Papillomaviridae / immunology*
  • Papillomavirus E7 Proteins
  • Recombinant Proteins
  • Repressor Proteins*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription, Genetic
  • Vaccines, DNA / immunology
  • Vaccines, DNA / therapeutic use*

Substances

  • Antigens, Neoplasm
  • Cancer Vaccines
  • E6 protein, Human papillomavirus type 16
  • H-2 Antigens
  • H-2K(K) antigen
  • H-2Kb protein, mouse
  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • Recombinant Proteins
  • Repressor Proteins
  • Vaccines, DNA
  • oncogene protein E7, Human papillomavirus type 16
  • Interferon-gamma