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The role of γc cytokines in the immune system and cancer immunotherapy
Ptáček, Bohumil ; Kovář, Marek (advisor) ; Adkins, Irena (referee)
Cytokines are proteins produced mostly by cells of hematopoietic origin and transduce signals via engaging cell surface receptors on either the cytokine-producing cells (autocrine signaling) or other target cells (paracrine signaling). Common cytokine receptor subunit (γc) cytokines are small glycoproteins belonging to type I cytokines with pleiotropic activities in both the innate and adaptive immune systems. All γc cytokines share a γc receptor subunit in their complete receptors. The first part of this thesis aims to summarize information about the biology of γc cytokines, their receptors, and their role in the immune system and its functions. The second part discusses the use of γc cytokines in cancer immunotherapy, presenting examples of particular γc cytokine therapies, and describes the approaches to improve the pharmacological features of γc cytokines or efficiently combine them with other immunotherapies and anticancer treatments. Keywords: γc cytokine, cytokine receptor, T cell, NK cell, cancer immunotherapy
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The importance of immunogenic cell death for modern tumor immunotherapy
Kubešová, Kateřina ; Šírová, Milada (advisor) ; Adkins, Irena (referee)
Immunogenic cell death is characterized by the release of molecules with damage-associated molecular patterns which can subsequently activate immune system. Only specific types of cell death can release these molecules. Classification of immunogenic cell death types and understanding of their initiation can be used for activation of the immune system against cancer cells. Simultaneously, it is necessary to understand different mechanisms, how the molecules with damage-associated molecular patterns work. Molecules with damage-associated molecular patterns which are studied the most, not only for their use in anticancer therapy, are type I interferons, calreticulin, high mobility group box 1 protein and heat shock proteins 70 and 90. Key words: immunogenic cell death, molecules with damage-associated molecular patterns, cancer, immunotherapy, type I interferons, calreticulin, high mobility group box 1 protein, ATP, heat shock protein 70, heat shock protein 90
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Immunomodulation of dendritic cells by adenylate cyclase toxin from B. pertussis
Jáňová, Hana ; Adkins, Irena (advisor) ; Brdička, Tomáš (referee)
Adenylate cyclase toxin (CyaA) produced by the causative agent of whooping cough Bordetella pertussis, is a key virulence factor important for colonization of the host. CyaA targets preferentially myeloid phagocytes expressing CD11b/CD18 integrin. By elevating cytosolic cAMP in the host cells, CyaA interferes with their phagocytic, chemotactic and oxidative burst capacities. Furthermore, CyaA modulates the secretion of cytokines and the maturation state in LPS-stimulated dendritic cells (DC) by affecting the expression of costimulatory molecules. In this study, we investigated the effects of CyaA on the capacity of murine bone-marrow DC to prime CD4+ and CD8+ T cells in response to ovalbumin epitopes delivered by the CyaA-AC- toxoid, as a model antigen. Further, we examined the possible impact of CyaA on the antigen uptake and processing for MHC class I and II-restricted presentation by DC, as we previously observed a decreased T cell stimulatory capacity of CyaA-treated DC in response to soluble ovalbumin. We found out that the high levels of cAMP generated by CyaA in LPS-stimulated DC account for the decreased presentation of ovalbumin epitopes carried by CyaA-AC- toxoid on MHC class I and II molecules, thereby impairing the CD8+ and CD4+ T cell responses. Whereas CyaA did not influence the...
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Non-small cell lung cancer immunotherapy based on dendritic cell vaccine pulsed with tumor cells killed by immunogenic cell death
Podzimková, Naďa ; Adkins, Irena (advisor) ; Ryška, Aleš (referee) ; Froňková, Eva (referee)
Lung carcinoma represents the leading cause of cancer mortality worldwide with dismal prognosis. Immunotherapy exploiting the patient's own immune system is booming along with dendritic cell (DC)-based immunotherapy in recent years. The use of DC-based vaccines for treatment of non-small cell lung cancer is, however, still limited with limited clinical efficacy despite the development of various techniques for the vaccine preparation. In this study, we focused on the development and characterization of DC-based vaccine pulsed with multi-antigenic tumor cells killed with high hydrostatic pressure (HHP) and cytotoxic hyperthermia (cHT). Both physical modalities induced immunogenic cell death which leads to DC activation and more efficient onset of antitumor immunity. The molecular apoptotic pathways activated upon HHP and cHT treatment in tumor cells were analyzed and the optimal conditions to achieve high mortality, high immunogenicity and low antigen degradation were identified. We also showed that the prophylactic vaccination of mice with cHT-treated tumor cells significantly delayed tumor growth and prolonged mice survival. DC pulsed with HHP or cHT-treated tumor cells exhibited phenotypic maturation, increased chemotactic migration, higher production of proinflammatory cytokines and increased...
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Immunomodulation of dendritic cells by adenylate cyclase toxin from B. pertussis
Jáňová, Hana ; Brdička, Tomáš (referee) ; Adkins, Irena (advisor)
Adenylate cyclase toxin (CyaA) produced by the causative agent of whooping cough Bordetella pertussis, is a key virulence factor important for colonization of the host. CyaA targets preferentially myeloid phagocytes expressing CD11b/CD18 integrin. By elevating cytosolic cAMP in the host cells, CyaA interferes with their phagocytic, chemotactic and oxidative burst capacities. Furthermore, CyaA modulates the secretion of cytokines and the maturation state in LPS-stimulated dendritic cells (DC) by affecting the expression of costimulatory molecules. In this study, we investigated the effects of CyaA on the capacity of murine bone-marrow DC to prime CD4+ and CD8+ T cells in response to ovalbumin epitopes delivered by the CyaA-AC- toxoid, as a model antigen. Further, we examined the possible impact of CyaA on the antigen uptake and processing for MHC class I and II-restricted presentation by DC, as we previously observed a decreased T cell stimulatory capacity of CyaA-treated DC in response to soluble ovalbumin. We found out that the high levels of cAMP generated by CyaA in LPS-stimulated DC account for the decreased presentation of ovalbumin epitopes carried by CyaA-AC- toxoid on MHC class I and II molecules, thereby impairing the CD8+ and CD4+ T cell responses. Whereas CyaA did not influence the...
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