Listeria-based vaccines can overcome tolerance by expanding low avidity CD8+ T cells capable of eradicating a solid tumor in a transgenic mouse model of cancer.
We have created a transgenic mouse with tissue-specific expression of the human papilloma virus (HPV) 16 E6 and E7 oncoproteins in the thyroid as a model of HPV transformed cancer. The expression of the transgenes results in the formation of palpable thyroid tumors. E7 is not expressed in other tissues but is expressed in medullary thymic epithelial cells, which have been implicated in the control of negative selection. We show that Listeria-based vaccines against E7 can induce the regression of solid implanted tumors in the transgenic mice, although at a lower frequency than in wild type (WT) mice. E7-specific CD8+ T cells induced in transgenic mice are of both lower avidity and lower frequency when compared to the WT mice. In this model, Listeria-based vaccines against E7 appear to be overcoming central tolerance by expanding low avidity CD8+ T cells specific for E7 that are not deleted during thymopoesis and can eliminate solid tumors.
Souders
Nicholas C
NC
Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Sewell
Duane A
DA
Pan
Zhen-Kun
ZK
Hussain
S Farzana
SF
Rodriguez
Alexander
A
Wallecha
Anu
A
Paterson
Yvonne
Y
D052685:Alphapapillomavirus; D000818:Animals; D000915:Antibody Affinity; D001428:Bacterial Vaccines / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines; D002460:Cell Line; D011905:Genes, ras; D008087:Listeria / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009856:Oncogene Proteins, Viral / Q000235:genetics; D050725:Papillomavirus E7 Proteins / Q000276:immunology; D010641:Phenotype
D001428:Bacterial Vaccines; D019496:Cancer Vaccines; C118860:E6 protein, Human papillomavirus type 6; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16