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Carbohydrate dimers in tumor immunotherapy
Krupová, Monika ; Bezouška, Karel (advisor) ; Ryšlavá, Helena (referee)
Carbohydrate dimers in tumor immunotherapy Monika Krupová (Department of Biochemistry, Faculty of Science, Charles University in Prague) One possible approach to tumor immunotherapy is an activation of killer lymphocytes through specific ligands for their surface receptors. CD69 is a molecule greatly widespread among various cells of haematopoietic origin. Since the physiological ligand for this receptor is still unknown, ligand mimetics are used for modulation of its activity. The mimetics tested in this work are based on monomeric or oligomeric carbohydrated attached through two different chemical groups to the central linker of varying length, giving rise to thiourea and triazole series. The ability to precipitate soluble NKR-P1 and CD69 receptors was evaluated in precipitation assays and the optimal length of the linker for NKR-P1 receptor was found to be decyl. On the other hand, cross-linking of CD69 is not so dependent on the length of the linker. The aim of this work was to describe in vitro effect of the tested compounds on cellular signalization, natural killing of leukemic cell lines and activation-induced apoptosis. Compounds of triazole series containing two disaccharides (GalNAc β1→4 GlcNAc) linked by a linker were found to have the strongest effect on the production of...
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Antigenome defines a selection of mutated tumor peptides driving tumor-specific T-cell response
Hadlová, Petra ; Drbal, Karel (advisor) ; Dibus, Michal (referee)
T cells, as an essential part of the adaptive immune system, play crucial role in eradication of tumor growth. T cells target, interact with and eventually annihilate the tumor cells in antigen- specific (Ag) manner. T cells interact with tumor cells via short epitopes bound to the major histocompatibility complex (MHC) molecules on the tumor cell surface. Tumor specific neoepitopes arise from random somatic mutations and constitute a part of the tumor antigenome. Antigenome comprises of two classes of antigens, tumor specific antigens (TSA) and tumor associated antigens (TAA). TSA are neoantigens carrying neoepitopes unique to each tumor. TAA are self-antigens presented by both tumor cells and non-transformed cells. Each tumor cell is able to develop numerous ways to evade the immune system consisting of T cells, NK cells, macrophages and other mechanisms employed. Despite that immunotherapy has shown a great potential in personalized medicine. The stratification of responsive patients is essential for effective and durable management of therapy in clinical practice. Methods are employed, which study existing reactive T cell clones, somatic mutations present in each patient, role of somatic mutations in tumor development and present neoepitopes. All these patient- specific features facilitate...
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Oncolytic viruses in cancer immunotherapy
Zupko, Jakub ; Bartůňková, Jiřina (advisor) ; Janovec, Václav (referee)
Oncolytic virotherapy is a field dedicated to exploiting viruses in the battle against cancer, where their specific cytolytic effects are sorely needed. This work focuses on the mechanisms and limitations of oncolytic virotherapy, on the recent advances in the field and on the potential oncolytic viruses hold for the future.
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Cytometric assay of antigen-specific T cell response in monitoring of BCG vaccine therapy
Hadlová, Petra ; Drbal, Karel (advisor) ; Kalina, Tomáš (referee)
Bladder carcinoma (BCa) is among the most common carcinomas in the Western world. Despite the availability of effective therapies, there is currently an urgent need to develop a stratification method, which would enable the accurate identification of patients responsive to therapy. In the theoretical part of my diploma project I describe the heterogeneity of BCa and the currently applied immunotherapeutic approaches. I specifically focused on the Bacillus Calmette-Guérin (BCG) vaccine instillation. For decades another use of BCG has been a prophylactic vaccination against tuberculosis (TB) infection. BCG serves as a model treatment because it is highly efficient when prescribed to the responsive patient. However, an effective stratification is yet to be developed for BCa and latent tuberculosis infection (LTBI) diagnosis and/or monitoring. In the experimental part of my project, I developed and tested a 10-parameter panel for T cell- specific activation test (TAT) applicable for a stratification of BCa patients as well as for the detection of LTBI. I tested the panel on positive controls using flow cytometry (FCM) method because it allows for detection and measurement of dozens of markers at a single cell level. It is easily applicable to available urine and blood samples obtained from BCa...
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Biological activity of IL-2/anti-IL-2 mAb immunocomplexes in vivo and their terapeutical potential
Hnilicová, Šárka ; Kovář, Marek (advisor) ; Grobárová, Valéria (referee)
IL-2 belongs to the family of c cytokines (IL-2, 4, 7, 9, 15, and 21) which are key regulators of lymphocyte homeostasis and function. They have the potential to promote lymphocyte proliferation and survival and thus overall enhance dominantly adaptive immune response. IL-2 is an autocrine/paracrine soluble factor produced mainly by activated T cells. Interestingly, the in vivo biological activity of IL-2 can be dramatically increased through complexing with certain anti-IL-2 mAbs and such IL-2/anti-IL-2 mAbs immunocomplexes selectively stimulate proliferation of distinct population of immune cells, depending on the clone of anti-IL-2 mAb used. IL-2/S4B6 mAb immunocomplexes are highly stimulatory for CD122high populations (memory CD8+ T and NK cells) and intermediately also for CD25+ populations (Treg and activated T cells), while IL-2/JES6-1 mAb immunocomplexes enormously expand solely CD25+ cells. Thus, IL-2 immunocomplexes possess a broad spectrum of potential therapeutic applications like tumor immunotherapy, vaccination, autoimmune diseases or transplantology.
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Mechanisms of specific immune response interactions with tumor cells.
Kaššák, Filip ; Hořejší, Václav (advisor) ; Černý, Jan (referee)
Interactions between the immune system and tumors have been among the highlights of present immunological research. An extensive body of new knowledge recently substantiated the long-presumed concept of cancer immunosurveillance. Immune system searches the organism for cells expressing tumor antigens or cellular stress signals and destroys them. T-cells, NK-cells and dendritic cells, as well as cytokine signaling and direct cell cytotoxicity play dominant role in this process. However, a fraction of nascent tumors can evade these mechanisms and create a dynamic equilibrium, gradually sculpting its phenotype by clonal selection. Eventually, tumor cells escape immune control by concealing themselves from recognition or by actively subjugating local immune response. This immunosubversion results in formation of immunosuppressive tumor microenvironment by recruiting protumorigenic cell populations, such as Treg cells, macrophages and myeloid derived suppressor cells. Soluble signaling molecules, as well as surface- expressed immune checkpoint molecules are exploited by tumor cells for inhibition of anti-tumor immunity. Highly effective therapeutic antibodies blocking these checkpoints have been developed for clinical use, with many more in current trials. Several other promising immunotherapeutic...
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Antigenome defines a selection of mutated tumor peptides driving tumor-specific T-cell response
Hadlová, Petra ; Drbal, Karel (advisor) ; Dibus, Michal (referee)
T cells, as an essential part of the adaptive immune system, play crucial role in eradication of tumor growth. T cells target, interact with and eventually annihilate the tumor cells in antigen- specific (Ag) manner. T cells interact with tumor cells via short epitopes bound to the major histocompatibility complex (MHC) molecules on the tumor cell surface. Tumor specific neoepitopes arise from random somatic mutations and constitute a part of the tumor antigenome. Antigenome comprises of two classes of antigens, tumor specific antigens (TSA) and tumor associated antigens (TAA). TSA are neoantigens carrying neoepitopes unique to each tumor. TAA are self-antigens presented by both tumor cells and non-transformed cells. Each tumor cell is able to develop numerous ways to evade the immune system consisting of T cells, NK cells, macrophages and other mechanisms employed. Despite that immunotherapy has shown a great potential in personalized medicine. The stratification of responsive patients is essential for effective and durable management of therapy in clinical practice. Methods are employed, which study existing reactive T cell clones, somatic mutations present in each patient, role of somatic mutations in tumor development and present neoepitopes. All these patient- specific features facilitate...
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Carbohydrate dimers in tumor immunotherapy
Krupová, Monika ; Bezouška, Karel (advisor) ; Ryšlavá, Helena (referee)
Carbohydrate dimers in tumor immunotherapy Monika Krupová (Department of Biochemistry, Faculty of Science, Charles University in Prague) One possible approach to tumor immunotherapy is an activation of killer lymphocytes through specific ligands for their surface receptors. CD69 is a molecule greatly widespread among various cells of haematopoietic origin. Since the physiological ligand for this receptor is still unknown, ligand mimetics are used for modulation of its activity. The mimetics tested in this work are based on monomeric or oligomeric carbohydrated attached through two different chemical groups to the central linker of varying length, giving rise to thiourea and triazole series. The ability to precipitate soluble NKR-P1 and CD69 receptors was evaluated in precipitation assays and the optimal length of the linker for NKR-P1 receptor was found to be decyl. On the other hand, cross-linking of CD69 is not so dependent on the length of the linker. The aim of this work was to describe in vitro effect of the tested compounds on cellular signalization, natural killing of leukemic cell lines and activation-induced apoptosis. Compounds of triazole series containing two disaccharides (GalNAc β1→4 GlcNAc) linked by a linker were found to have the strongest effect on the production of...
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