National Repository of Grey Literature 6 records found  Search took 0.00 seconds. 
Wnt/beta-catenin and mTOR signaling in regulation of T-cell phenotype and cytotoxic activity for adoptive cellular immunotherapy of cancer
Stakheev, Dmitry ; Smrž, Daniel (advisor) ; Černý, Jan (referee) ; Říhová, Blanka (referee)
1. Abstract (EN) The adoptive cellular immunotherapy (ACI) based on ex vivo produced T cells is a modern treatment modality of cancer. However, the ex vivo production of T cells with high therapeutic efficacy is far to be well established. Wnt/β-catenin and mTOR signaling have been shown to affect both cancer cells and immune cells. Therefore, the modulation of these pathways seems to be perspective for the production of T cells with superior therapeutic efficacy. The aim of our project was to investigate, how interventions into Wnt/β-catenin and mTOR signaling during the ex vivo production of tumor-associated antigen-specific T cells could improve the production of T cells with a desired and controlled phenotype that would best fit for use in ACI of cancer. In the first part of our study, we investigated the role of Wnt/β-catenin inhibition by XAV939 on cancer cell elimination by lymphocytes from patients with localized biochemically recurrent prostate cancer (BRPCa). We found that preconditioning BRPCa lymphocytes with 5 µM XAV939 accelerated the elimination of LNCaP and PC3 cells during the coculturing. However, during subsequent re-coculturing with fresh LNCaP cells, BRPCa lymphocytes were no longer able to eliminate cancer cells unless coculturing and re-coculturing were performed in the presence of...
Wnt/beta-catenin and mTOR signaling in regulation of T-cell phenotype and cytotoxic activity for adoptive cellular immunotherapy of cancer.
Stakheev, Dmitry ; Smrž, Daniel (advisor) ; Černý, Jan (referee) ; Říhová, Blanka (referee)
1. Abstract (EN) The adoptive cellular immunotherapy (ACI) based on ex vivo produced T cells is a modern treatment modality of cancer. However, the ex vivo production of T cells with high therapeutic efficacy is far to be well established. Wnt/β-catenin and mTOR signaling have been shown to affect both cancer cells and immune cells. Therefore, the modulation of these pathways seems to be perspective for the production of T cells with superior therapeutic efficacy. The aim of our project was to investigate, how interventions into Wnt/β-catenin and mTOR signaling during the ex vivo production of tumor-associated antigen-specific T cells could improve the production of T cells with a desired and controlled phenotype that would best fit for use in ACI of cancer. In the first part of our study, we investigated the role of Wnt/β-catenin inhibition by XAV939 on cancer cell elimination by lymphocytes from patients with localized biochemically recurrent prostate cancer (BRPCa). We found that preconditioning BRPCa lymphocytes with 5 µM XAV939 accelerated the elimination of LNCaP and PC3 cells during the coculturing. However, during subsequent re-coculturing with fresh LNCaP cells, BRPCa lymphocytes were no longer able to eliminate cancer cells unless coculturing and re-coculturing were performed in the presence of...
Tumor-infiltrating T cells and their role in adoptive cell immunotherapy of cancer
Střížová, Zuzana ; Smrž, Daniel (advisor) ; Vannucci, Luca Ernesto (referee) ; Posová, Helena (referee)
Cancer immunotherapy has become a leading treatment modality in metastatic diseases. Although this novel therapy has changed the therapeutic algorithms and patients' outcomes in multiple malignancies, certain proportions of patients still fail to respond to these approaches. In our studies, we aimed to address the main mechanisms of tumor resistance to cancer immunotherapy. We have systematically defined the main challenges in adoptive cell transfer. We have focused on two key mechanisms of the tumor resistance to immunotherapy: poor trafficking of adoptively transferred immune cells into tumors, and the death receptor-induced apoptosis of the tumor-infiltrating immune cells. In our work, we have gone beyond the tumor tissue and searched for the immune cell populations and novel targets that would help to challenge the two mechanisms of resistance. Our data uncovered the therapeutic potential of the paratumoral tissue compartments and, thus, provided new avenues on how to challenge solid tumors by immunotherapy.
Tolerogenic dendritic cells as a novel cell-based therapy in type 1 diabetes
Kroulíková, Zuzana ; Funda, David (advisor) ; Smrž, Daniel (referee)
Utilization of tolerogenic dendritic cells (tolDCs) as a cell-based therapy represents a promising strategy in treatment of autoimmune diseases including type 1 diabetes (T1D). Numerous protocols have been established to generate tolDCs ex vivo and their therapeutic effect has been demonstrated in animal models of autoimmune diseases. In this thesis we compared three different variants of such protocols which are based on the combined treatment of bone marrow- derived DCs with vitamin D and dexamethasone applied at different time points of their maturation towards tolDCs. We assessed the efficiency of these protocols in regards of their effect on the expression of co-stimulatory molecules CD40, CD80, CD86, and MHC II and the chemokine receptor CCR7 on the surface of tolDCs. Then, we evaluated the migration pattern of antigen unloaded tolDCs in vivo as well as their effect on the induction of immune responses and cell proliferation of lymph node cells. This was achieved by labelling of tolDCs with membrane dye PKH26 and by following their migration path by flow cytometry after intraperitoneal (i.p) or subcutaneous (s.c.) injection into either left or right side of the body. On day 1, 3, 5, 7, and 9, the presence of PKH26+ tolDCs was examined in spleen, pancreatic, mesenteric, inguinal and axillary...
Surface expression of Tim-3 inhibitory molecule on antigen-specific CD8+ T cells expanded in vitro using dendritic cells for cell-based cancer immunotherapy
Svobodová, Hana ; Smrž, Daniel (advisor) ; Funda, David (referee)
Cancer is the second most common cause of death in the world, and the number of people with the disease increases each year. The therapy of the disease currently stands on four pillars; surgery, chemotherapy, radiotherapy, and immunotherapy. Through the past few years, immunotherapy has become the fastest developing treatment modality. However, despite its unprecedented efficacy in some patients, the majority of patients still does not respond to the therapy. Therefore, there is a need to investigate the mechanisms that make immunotherapy inefficient. Cell-based cancer immunotherapy is the treatment modality which uses live ex vivo-produced tumor-targeting immune cells to treat cancer. One of the mechanisms that may compromise its therapeutic efficacy is the expression of inhibitory molecules on the surface of the produced immune cells. Tim-3 is the inhibitory molecule which attracts attention in recent years. Tim-3 expression in the tumor cells and the tumor-infiltrating immune cells is often associated with worse prognosis and more aggressive forms of the disease. However, its role in the in vitro or ex vivo-produced immune cells is difficult to predict. In this work, an in vitro study model which is based on in vitro-produced antigen-specific CD8+ T cells with high expression of Tim-3 has been...
Phosphatidylserine and phospholipid scramblase in mast cell signaling
Smrž, Daniel ; Dráber, Petr (advisor) ; Bezouška, Karel (referee) ; Šebo, Peter (referee)
6. CONCLUSIONS 1. We found that mast cell stimulation can induce PS externalization in the absence of secretory response. 2. We identified GPI-APs as molecules whose engagement can induce sustained and reversible non-apoptotic PS externalization. 3. GPI-AP-induced PS externalization was determined as non- apoptotic and distinct from the FceRl-induced PS externalization. 4. The effect of multiple triggering on PS externalization was additive and dependent on a tlpe of stimulus and cells engaged. 5. We identifred PLSCR1 as a molecule that becomes tyrosine phosphorylated in mast cells stimulated through GPI-APs. 6. We found that the PLSCR1 tyrosine phosphorylation is not associated with mast cell secretory response' and with GPI-AP- or FceRl-induced non-apoptotic PS externalization. 7. Using confocal microscopy and electron microscopy visualization of PLSCR1 in the course of mast cell activation we found that PLSCR1: (1) is not co-localized with extemalized PS, (2) is not co- localized with aggregated Thy-l.l or FceR[, and (3) does not form self-aggregates. 8. We děřelóped a modifred one-tube semi-nested PCR-ELISA. The modified assay showed higher sensitivity and specificity than the conventional hybridization-based and a modified semi-nested- based PCR-ELISA. Due to its versatility and robustness, the...

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4 Smrž, Dominik
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