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Significance of MHC class I molecules in antitumor immunity
Lhotáková, Karolína ; Poláková, Ingrid (advisor) ; Horníková, Lenka (referee)
The main function of the major histocompatibility complex class I (MHC I) glycoproteins is to present antigenic peptides to CD8+ T lymphocytes. Majority of the peptides displayed by this complex come from cell protein degradation and CD8+ T lymphocytes do not respond to them. Tumor development leads to alterations in protein production and new epitopes are generated which impacts peptide repertoire presented by MHC I glycoproteins on the cell surface. Peptides originated from tumor antigens activate CD8+ T lymphocytes and induce anti-tumor immune responses. Decreased surface expression of MHC I molecules is a common phenomenon in tumor cells that prevents effective immune response. As appropriate MHC I expression level on tumor cells is needed for their effective killing by T cell-mediated immune response, downregulation of the MHC I expression may lead to the selection of tumor cells with decreased MHC I level. This downregulation can be either reversible or irreversible, affecting not only the expression of genes encoding the light and heavy chains of MHC I molecules, but also genes of the antigen-processing machinery (APM). Immunotherapeutics focused on the induction of surface expression of MHC I molecules often have other unfavorable impacts on the immune system. Therefore, a new approach is...
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Gene Immunotherapy of Cancer: DNA Vaccines against HPV 16
Poláková, Ingrid
of PhD. Thesis Gene Immunotherapy of Cancer: DNA Vaccines against HPV 16 Mgr. Ingrid Poláková Cervical carcinoma (CC) represents the second most frequent cancer in women, mostly associated with human papillomavirus (HPV) infection. Nowadays, two prophylactic vaccines, protecting against HPV 16 and HPV 18, are licensed. Nevertheless, development of therapeutic vaccines is desirable to eliminate current HPV infections and to treat progressing tumours. Suitable targets for vaccination are viral E6 and E7 oncoproteins. Since its discovery, DNA vaccination has become an effective strategy for development of vaccines against cancer including CC. Unfortunately, the immunogenicity of DNA vaccines in large animals and particularly in humans is low. Therefore, several ongoing studies are focused on strategies enhancing the efficacy and safety of DNA vaccines. In this work, the immunogenicity of DNA vaccines against HPV 16 delivered by a gene gun was evaluated after the fusion of the E7 and E6 genes with GUS. The increased steady-state level of the E7GGG.GUS deletion mutants and the GUS.E7GGG fusion protein enhanced the production of E7-specific antibodies after immunisation with these vaccines but did not improve the CTL response. Joining of the signal sequence with GUS.E7GGG led to ER-localisation of the...
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Genová imunoterapie nádoru: DNA vakcíny proti HPV16
Poláková, Ingrid ; Šmahel, Michal (advisor) ; Hejnar, Jiří (referee) ; Reiniš, Milan (referee)
of PhD. Thesis Gene Immunotherapy of Cancer: DNA Vaccines against HPV 16 Mgr. Ingrid Poláková Cervical carcinoma (CC) represents the second most frequent cancer in women, mostly associated with human papillomavirus (HPV) infection. Nowadays, two prophylactic vaccines, protecting against HPV 16 and HPV 18, are licensed. Nevertheless, development of therapeutic vaccines is desirable to eliminate current HPV infections and to treat progressing tumours. Suitable targets for vaccination are viral E6 and E7 oncoproteins. Since its discovery, DNA vaccination has become an effective strategy for development of vaccines against cancer including CC. Unfortunately, the immunogenicity of DNA vaccines in large animals and particularly in humans is low. Therefore, several ongoing studies are focused on strategies enhancing the efficacy and safety of DNA vaccines. In this work, the immunogenicity of DNA vaccines against HPV 16 delivered by a gene gun was evaluated after the fusion of the E7 and E6 genes with GUS. The increased steady-state level of the E7GGG.GUS deletion mutants and the GUS.E7GGG fusion protein enhanced the production of E7-specific antibodies after immunisation with these vaccines but did not improve the CTL response. Joining of the signal sequence with GUS.E7GGG led to ER-localisation of the...
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