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Immunoprotective character of polymer cytotoxic drugs
Šírová, Milada ; Říhová, Blanka (advisor) ; Turánek, Jaroslav (referee) ; Rabišková, Miloslava (referee)
18 I. INTRODUCTION Cancer is a serious health problem worldwide. In economically developed countries, it is a second most frequent cause of death after cardiovascular dis- eases, and the number of oncological patients continuously increases with the increasing age of population. The mainstay of cancer therapy is combination of surgery, radiation and chemotherapy. Whilst surgery and radiation are relatively precise and suitable to achieve a local control over the tumor, chemotherapy exerts a systemic ef- fect. These three modalities, when properly combined and sequenced, can cure a substantial number of hematological cancers and a smaller, but still significant subset of various solid tumors. Most cytostatic/cytotoxic drugs that are now in common use target the cells with high proliferation rate. The non-selective character of chemotherapy leads to increased toxicities towards normal rapidly proliferating cells. This means that the drugs have to be used at suboptimal doses, leading to development of (multi)drug resistance, metastatic disease and, eventually, to failure of the therapy. Innovative therapeutic strategies need to be developed in order to achieve better treatment outcome. For that purpose, several approaches are be- ing applied. First, sophisticated genomic and proteomic research could identify...
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Humoral response to heat shock proteins in patients with juvenile idiopathic arthritis and in relation to complications following transplantation of hematopoietic stem cells
Zlacká, Denisa ; Hromadníková, Ilona (advisor) ; Říhová, Blanka (referee) ; Posová, Helena (referee)
ln 0\If worlu w~ aimN to.rudy the ml~ of ll! H>p60. U bol'i< Hsp6) md .u=;- indocibl~ ll! Hsp70 in pathogmesis of juvmil~ idiopathi<: anhriti, (JlA) md !haom:ot<>id anhriti, (RA), ln tbe.rudy of hUlllOflll =pons.r ~gainsl ll! Hsp60, M. 00.1:. H'p65 md rh Hsp70 w= found sigoificml rl«.·atM l~..,ls of mTi~, against -iodurib~ Hsp70 in a tot:tl cohon ofp:lTi..u, "~Ih J1'. whm COII1pMM with br:ollhy indi\idWS. 1k pr~\':oIroc~ of mTi-Hsp70 antibodies is much high<f in JlA pati<n15 wbro COIllp:If~d "ith br:olthy controls suggesTing tbeir possiblr rol~ in patbological mrclwlism oftbe ~ ln Ibr study of ~ ~,ioo of ioduribl~ Hsp70 W~ dtt<-crN high mrrubrnJt a~,ion of Hsp70 00 fibrob1asl-liU .yn,,,"i:ol c~Us dtri"N ftom syno\i. aff..,Tnl by allloimmunr inflamm:llion. W~ 5Cfffnr<l tbe 1""""""" of Hsp =q>IOI'S 1ikr TI1t2 2I!d TI.R4. CDl4. CDM. CD40 :md CD91 :os w~U ., thriI associaTion "ith inducibl~ Hsp71l OD RA <krj\"N fibrobbst-hl:~ syno,-i:Il cdls. 80th .ynovi.>! cdl, 2I!d skin fibroblasts aprrsstd bigh ~",l, of cdl.ruďac~ CD9!. bo\\'~""-_ DO Ol lov, b",ls of otbrr rtttplOf1i W~ sprrul:IlN tIw indociblr &p70 rd~2Sr<I from infIamrd S)'OO''ia1 1~ mighl br c:tpturt<l 0010 tbe ""U ,UĎ""" of 'yn<l\ia! ""U, from tbe txtrac~llular sp:Ic~ \;" CD91 fm'Jlt()[ ln tbe ,rudy of htm10ral respon= agairul tbe brat sbock...
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The clinical relevance of immunogenic cell death associated signalling and molecules in cancer therapy
Holíček, Peter ; Palich Fučíková, Jitka (advisor) ; Říhová, Blanka (referee) ; Starková, Júlia (referee)
The clinical relevance of immunogenic cell death-associated signaling and molecules in cancer therapy The capacity of cancer cells to induce anticancer immune responses relies on multiple factors, including the antigenic repertoire of cancer cells and their ability to provide adjuvant signals, as represented by danger-associated molecular patterns (DAMPs), which are exposed and released by malignant cells during immunogenic cell death (ICD). The release and secretion of DAMPs can orchestrate the activation of innate and adaptive tumor-targeting immunity, resulting in tumor regression. Various chemotherapies, radiation therapy, physical modalities, and targeted anticancer agents have been described as potent ICD inducers, which besides being directly cytotoxic, can activate clinically relevant anticancer immune responses. Therefore, patients whose tumor microenvironment (TME) is shows defective DAMP release or downstream DAMP-sensing signaling pathways do not fully benefit from ICD-inducing treatments, which can lead to overall therapeutic failure. My dissertation contributes to this field by exploring the impact of ICD on the development of innate anticancer immune responses, with a particular focus on natural killer (NK) cells, showing that surface-exposed calreticulin (ecto-CALR) positively impacts the...
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Immunological aspects of head and neck cancer in relation to etiology
Koucký, Vladimír ; Bouček, Jan (advisor) ; Říhová, Blanka (referee) ; Smilek, Pavel (referee)
Tumor immunology is a progressively developing, multidisciplinary branch of biology. Results of basic research have already been successfully translated to clinical practice. The immediate success of new immunotherapeutic drugs, especially immune checkpoint inhibitors, has further supported the expansion of basic and clinical research in this field. In the case of head and neck squamous cell carcinoma (HNSCC), some immune system elements, such as CD8+ T cells, were shown to play an important role in the progression of the disease. Importantly, HNSCC is a diverse group of diseases, and a significant number of the tumors are induced by high-risk strains of human papillomavirus (HPV). HPV-associated tumors (HPV+ ) respond better to standard therapy, and the immune system was shown to be one of the crucial factors in this phenomenon. We focused on the analysis of phenotype, function, and prognostic value in tumor-infiltrating immune cells in HNSCC patients regarding the HPV status of the tumor. We were able to detect CD8+ tumor-infiltrating T cells reacting to HPV16 antigens in the majority of HPV+ oropharyngeal cancers. Moreover, activity of these T cells was enhanced after blockade of both PD-1 and TIM-3 immune-checkpoint pathways, supporting a concept of combined immunotherapy. In our...
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Checkpoint blockade in cancer immunotherapy
Vacková, Julie ; Šmahel, Michal (advisor) ; Černý, Jan (referee) ; Říhová, Blanka (referee)
The immune checkpoint blockade is a novel approach of cancer therapy, which markedly enhanced treatment efficacy of several cancer types. However, the frequency of cancer patients non-responding to this treatment is high. Establishment of predictive markers to distinguish patients suitable for the immune checkpoint blockade would enhance the number of patients receiving benefit from the therapy. This dissertation thesis focuses on the enhancement of efficacy of immune checkpoint inhibitors (ICIs) and predictive markers in experimental models of mouse tumours induced by TC-1 and TC-1/A9 cell lines and its clones with deactivation of interferon (IFN)-γ signalling (TC-1/dIfngr1 and TC-1/A9/dIfngr1), or CD80 molecule (TC-1/dCD80-1). IFN-γ is presumed to be the main inducer of programmed death ligand 1 (PD-L1) and a major histocompatibility complex I (MHC-I). Moreover, PD-L1 expression may predict sensitivity to PD-1/PD-L1 blockade. Non-functional IFN-γ signalling or downregulated MHC-I expression has been associated with resistance to ICIs in some patients. We found that IFNs type I (IFN-α and IFN-β) induced the expression of PD-L1 and MHC-I on TC-1/A9/dIfngr1 tumour cells with reversible downregulation of both molecules. We also showed that deactivation of IFN-γ signalling in TC-1/A9 cells was not a...
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Immuno-biological Aspects of Head and Neck Squamous Cell Carcinoma
Bouček, Jan ; Říhová, Blanka (advisor) ; Fučíková, Terezie (referee) ; Šlapák, Ivo (referee)
The process of tumorigenesis is conditioned by change or the series of changes at a gene level. The development of cancer is largely pre-ordained by this change, but very important role is played by other factors. In case of solid tumors it is mainly a tumor microenvironment, where the tumor cells are in contact with stromal cells, especially fibroblasts, and immune cells. Tumor microenvironment can also critically modify the nature and intensity of anti- tumor immune response. Squamous cell carcinomas of the head and neck are the sixth most common cancer, which affect each year more than half a million patients worldwide. Despite advances and improvements in all treatment modalities, achieved therapeutic results even in Western countries are not satisfactory and remain at approximately the same values for several decades. At prezent, the 5 years survival rate, regardless of the location and stage of disease, is approximately only 40%. In the prezented work the immunological and biological aspects of squamous cell carcinoma of the head and neck are discussed. It summarizes the recent findings on the molecular basis of the behavior of tumor cells and the influence and significance of regulation of the immune system for the clinical course of disease and the modern therapeutic approaches.
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Polymeric-drug Conjugates in Treatment of Head and Neck Squamous Cell Carcinoma
Betka, Jaroslav ; Říhová, Blanka (advisor) ; Prausová, Jana (referee) ; Reiniš, Milan (referee)
Malignant diseases are after cardiovascular diseases the second most common cause of death in the developed countries. The number of patients newly diagnosed with cancer is constantly rising, on average by 2.5% yearly. This trend also applies to squamous cell carcinoma of the head and neck, which is the sixth most common oncological disease. Its occurrence is most influenced by two external risk factors: smoking and abuse of alcohol; latest research indicates that for the emergence of neoplasia is crucial not only the amount of and duration of the use of a harmful substance but also the time of day when a harmful substance is used as well as psychological dependence on the substance. But recently, we are witnessing growth of the frequency of occurrence of the squamous cell carcinoma of the pharynx with non-smokers and younger age groups in connection with presence of the HPV infection in tumor. The forms of so far most commonly used anticancer therapy (surgery, radiotherapy, chemotherapy) have, despite progressions over the last decades, lead to significant improvement only with some types of cancer but in the case of squamous cell carcinoma of the head and neck is the total probability of five-year survival still low, approximately 40%. Therefore we are turning our attention to the new forms of...
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Glycobiology of the head and neck cancer
Valach, Jaroslav ; Smetana, Karel (advisor) ; Dřízhal, Ivo (referee) ; Říhová, Blanka (referee)
iii Abstract Glycobiology represents a very progressive subject of cell biology. Protein-saccharide interactions play not only supporting and cell organization role, but they also represent medium for information storage and its decoding. Galectins, group of animal lectins (saccharide-binding proteins), which have selective affinity to ß-galactosides, are multifactorial molecules. They participate in cell-cell and cell-matrix interaction, transmembrane signaling, apoptosis, pre- mRNA splicing and are also present in various types of carcinomas. High expression of galectin-1 has been detected in cancer stroma originated from squamous cell epithelium. In the previous study we established that the fibroblasts - myofibroblasts transition, apart from the known TGF- beta, is also induced by galectin-1. We compared relationship between galectin-1 expression, presence of myofibroblasts and gene expression in tissue samples from patients with head and neck squamous cell carcinoma. Cancer stroma with myofibroblasts was rich in galectin-1 expression in comparison with stroma without myofibroblasts. Moreover, we used microarray analysis (ILLUMINA) to compare the whole genome transcriptome from samples with and without presence of galectin-1. High expression of galectin-1 in tissue samples corresponded with expression...
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