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Interaction between NKT and myeloid derived suppressor cells and antitumour immunity
Straňavová, Lucia ; Reiniš, Milan (advisor) ; Holáň, Vladimír (referee)
Myeloid- derived suppressor cells (MDSCs) are a heterogeneous population of cells, which plays an important role in the suppression of anti-tumor immune responses. NKT cells represent an additional heterogeneous cell population that plays a crucial role in the regulation of immune responses. It shows that MDSCs and NKT cells may be similar to other populations imunoregulatory cells interact with each other and influence their functions. These interactions are important regulatory factor that may contribute to activation and to suppress anti-tumor immunity. Through interactions with type I NKT cells could differentiate these immunosuppressive MDSCs to immunogenic APC, which could form the basis for immunotherapeutic vaccine. All interactions between the NKT and MDSCs but have a positive effect of imunoregulatory. Interaction between MDSCs and CD4 + NKT cells II. type are immunosuppressive and may subsequently suppress the activity of cytotoxic T-lymphocyte (CTL). In some tumor models it was found that the immunosuppressive nature may also be interactions between MDSCs and type I NKT cells He had, however, alleviate the use of all-trans-retinol acid (ATRA), which induces differentiation of MDSCs.
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Immunogenic cell death in tumor specimens in the clinics
Fejfarová, Adéla ; Drbal, Karel (advisor) ; Büchler, Tomáš (referee)
Tumor development and growth are under the control of the immune system in the human body. Danger-associated molecular pattern (DAMP) molecules trigger the anti-tumor response by binding to pattern recognition receptor (PRR) on myeloid cells which in turn activate an adaptive immune system. DAMP molecules are released from cancer cells during a process of immunogenic cell death (ICD) which is a form of regulated cell death (RCD). ICD is induced by a variety of treatments in experimental settings as well as by therapeutic modalities commonly used in medicine. A typical DAMP marker of ICD is calreticulin which is translocated from the endoplasmatic reticulum to the plasma membrane attached to the CD91 receptor. Another marker is the nuclear protein HMGB1 which is released into the tumor environment at the later stage of ICD. This bachelor thesis describes a variety of detection methods and the results of DAMP externalization after ICD induction in vitro in cancer cell lines and in tumor specimens from cancer patiens. Moreover, the link between DAMP molecules and cancer patient survival is discussed. Last, it also summarizes the current status of clinical trials concerning ICD. Keywords tumor, antitumor immunity, cell death, adjuvans, DAMP, chemotherapeutics, immunogenic cell death, clinical trials
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Immunogenic cell death
Šímová, Michaela ; Drbal, Karel (advisor) ; Javorková, Eliška (referee)
According to the danger model, the immune system is activated by endogenous molecules known as danger-associated molecular patterns (DAMP) that are externalized from the interior of a dying cell to the cell surface or released into the extracellular space. Due to the loss of plasma membrane integrity a necrotic cell death as well as several types of proinflammatory programmed cell death are considered to be immunogenic, whereas apoptosis, on contrary, has been initially defined as a tolerogenic type of cell death. However, under certain circumstances, the immune response can be initiated by an apoptotic cell after exnternalization of DAMP molecules by newly described secretory pathways. This phenomenon was observed on tumor cells as a result of some widely used therapeutic modalities and is known as immunogenic cell death (ICD). Nomenclature of selected types of cell death is part of this thesis. The aim of this bachelor thesis is to provide an evidence of the experimental support for ICD theory during in vivo initiation of the immune response. I will evaluate the correlation between ICD and the induced exposure of DAMP molecules on the surface of tumor cells or their secretion to the extracellular space.
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Modification of murine tumor cell lines with CRISPR/Cas9 system and their characterization
Lhotáková, Karolína ; Poláková, Ingrid (advisor) ; Brábek, Jan (referee)
MHCI molecules are constitutively expressed in all nucleated cells and play a key role in antigen presentation to CD8+ T lymphocytes. One of the tumor immune evasion strategies is MHCI expression downregulation. This leads to an impaired recognition of tumor antigens by CD8+ T lymphocytes that are unable to start the immune response. Since the MHCI expression downregulation occurs in up to 90 % of some tumors it is neccesary to have a clinical relevant tumor model without a MHCI surface expression that would be used for testing of immunotherapeutic approaches. This thesis describes a production of new model cell lines of TC-1 tumor cells with irreversibly downregulated MHCI. That was achieved by an inactivation of B2m, which is a part of MHCI, by gene editing using CRISR/Cas9. The B2m inactivation was confirmed by flow cytometry, western blot and sanger sequencing of single alleles. The inactivation slowed down the cell growth for both in vitro and in vivo. The cell metastatic activity was not affected. The tumors established by cells without the B2m expression are not sensitive to DNA vaccine against HPV16 E7 oncoprotein by a pBSC/PADRE.E7GGG vaccine. The main effector function against these tumors possess the NK1.1+ cells. In a therapeutic vaccination experiment it was repeatedly achieved of...
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Immunogenic cell death
Šímová, Michaela ; Drbal, Karel (advisor) ; Javorková, Eliška (referee)
According to the danger model, the immune system is activated by endogenous molecules known as danger-associated molecular patterns (DAMP) that are externalized from the interior of a dying cell to the cell surface or released into the extracellular space. Due to the loss of plasma membrane integrity a necrotic cell death as well as several types of proinflammatory programmed cell death are considered to be immunogenic, whereas apoptosis, on contrary, has been initially defined as a tolerogenic type of cell death. However, under certain circumstances, the immune response can be initiated by an apoptotic cell after exnternalization of DAMP molecules by newly described secretory pathways. This phenomenon was observed on tumor cells as a result of some widely used therapeutic modalities and is known as immunogenic cell death (ICD). Nomenclature of selected types of cell death is part of this thesis. The aim of this bachelor thesis is to provide an evidence of the experimental support for ICD theory during in vivo initiation of the immune response. I will evaluate the correlation between ICD and the induced exposure of DAMP molecules on the surface of tumor cells or their secretion to the extracellular space.
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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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Interaction between NKT and myeloid derived suppressor cells and antitumour immunity
Straňavová, Lucia ; Reiniš, Milan (advisor) ; Holáň, Vladimír (referee)
Myeloid- derived suppressor cells (MDSCs) are a heterogeneous population of cells, which plays an important role in the suppression of anti-tumor immune responses. NKT cells represent an additional heterogeneous cell population that plays a crucial role in the regulation of immune responses. It shows that MDSCs and NKT cells may be similar to other populations imunoregulatory cells interact with each other and influence their functions. These interactions are important regulatory factor that may contribute to activation and to suppress anti-tumor immunity. Through interactions with type I NKT cells could differentiate these immunosuppressive MDSCs to immunogenic APC, which could form the basis for immunotherapeutic vaccine. All interactions between the NKT and MDSCs but have a positive effect of imunoregulatory. Interaction between MDSCs and CD4 + NKT cells II. type are immunosuppressive and may subsequently suppress the activity of cytotoxic T-lymphocyte (CTL). In some tumor models it was found that the immunosuppressive nature may also be interactions between MDSCs and type I NKT cells He had, however, alleviate the use of all-trans-retinol acid (ATRA), which induces differentiation of MDSCs.
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