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

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-γ resulted in an upregulation of MHC class I molecules in these cells, but after IFN-γ 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.