Mutation in the immunodominant epitope of the HPV16 E7 oncoprotein as a mechanism of tumor escape.
Infection with high-risk types of human papillomavirus (HPV) can cause the development of malignant tumors. To study mechanisms responsible for immune escape of tumor cells infected with HPV16, we previously used mouse oncogenic TC-1 cells producing HPV16 E6 and E7 oncoproteins to derive TC-1 clones resistant to immunization against E7. We have found immunoresistance of the clones to correlate with the point mutation in the E7 oncogene, which resulted in the N53S substitution in the immunodominant epitope RAHYNIVTF (aa 49-57). Here, we have shown that this mutation reduced stabilization of H-2D(b) molecules on RMA-S cells and eliminated immunogenicity of E7. The resistance of TC-1 clones was E7-specific as immunization against E6 inhibited tumor growth. Transduction of the TC-1/F9 clone carrying the mutated epitope with the wild-type E7 gene restored susceptibility to immunization against E7. Our results suggest that mutagenesis of tumor antigens can lead to the escape of malignant cells and should be considered in the development and evaluation of cancer immunotherapy.
Smahel
Michal
M
Department of Experimental Virology, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20 Prague 2, Czech Republic. smahel@uhkt.cz
Tejklova
Pavla
P
Smahelova
Jana
J
Polakova
Ingrid
I
Mackova
Jana
J
D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry; D000939:Epitopes / Q000737:chemistry; D005260:Female; D006183:H-2 Antigens / Q000737:chemistry; D064532:Histocompatibility Antigen H-2D; D006801:Humans; D016056:Immunodominant Epitopes / Q000737:chemistry*; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D015513:Oncogene Proteins / Q000737:chemistry; D009856:Oncogene Proteins, Viral / Q000737:chemistry* / Q000235:genetics*; D050725:Papillomavirus E7 Proteins; D017354:Point Mutation
D000951:Antigens, Neoplasm; D000939:Epitopes; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D016056:Immunodominant Epitopes; D015513:Oncogene Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16