Exploring the Potential for More Effective Cancer Treatment: Investigations on Tumour Immunity and Cancer Stem Cells in Breast Cancer and Melanoma

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URI: http://hdl.handle.net/10900/138212
Dokumentart: PhDThesis
Date: 2025-02-28
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biologie
Advisor: Pawelec, Graham (Prof. Dr.)
Day of Oral Examination: 2023-02-28
DDC Classifikation: 500 - Natural sciences and mathematics
License: http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=de http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=en
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Die Dissertation ist gesperrt bis zum 28. Februar 2025 !


This thesis aimed to better understand the current hurdles preventing more effective cancer treatment. This was investigated from two angles, cancer stem cells (CSCs) and tumour immunity. CSCs possess the capacity of self-renewal and the ability to give rise to progeny with the potential to proliferate and differentiate. As such, these cells are able to differentiate into different lineages and clones that make up the tumour mass and as such are claimed to represent a major form of resistance to conventional therapeutic approaches which must be overcome in order to achieve better cancer treatments. In melanoma, the identification and characterization of CSCs remains incomplete, with many studies reporting conflicting findings. To bridge this gap in understanding, the expression of markers which identify CSCs in melanoma on a putative basis (ALDH1A1, ABCG2, CD44v7/8, CD44v10, CD133, CD271 and Nestin) was studied in vitro in cell lines, in situ in tissues and in healthy control samples. It was observed that CSC markers were expressed by the majority of melanoma cells in vitro and in situ, but they were also found on healthy differentiated tissues and cells, indicating that they are not specific markers for cancer stem cells. Furthermore, the clinical role of selected CSC markers was investigated in melanoma tissues, revealing that high levels of ABCG2 were associated with advanced clinical stage, while higher expression of both ABCG2 and CD133 correlated with poorer patient survival. These data pave the way for the validation of these moieties as therapeutic targets for melanoma in future. Despite the recent expansion in the use of immunotherapy for many cancer types, it is still not a standard treatment for breast cancer. To assist in the clinical implementation of immunotherapy in breast cancer, this investigation sought to characterise the immune systems of breast cancer patients with the aim of identifying therapeutic targets and prognostic indicators in the following settings 1) patients compared to healthy women, and 2) under treatment with different forms of therapy. To do this, the frequencies of myeloid and lymphoid immune cells at different stages of differentiation were investigated in the peripheral blood of breast cancer patients using multiparametric flow cytometry. Functional in vitro assays were additionally employed to investigate mechanisms of immune function. The results revealed that 4 compared with healthy women of the same age, breast cancer patients have significantly elevated frequencies of cells with a myeloid-derived suppressor cell phenotype in the blood as well as higher levels of T cells at earlier stages of differentiation. Furthermore, functional testing showed that myeloid cells from breast cancer patients more potently suppressed autologous T cell proliferation than cells from healthy women, which was found to be partly mediated by the release of reactive oxygen species. The peripheral immune system was then investigated for association with breast cancer prognosis in patients under different therapeutic settings. This study found that the levels of circulating T cells in patients treated with high-dose paclitaxel-containing therapy correlated with patient survival. By contrast, patients treated with high-dose cyclophosphamide-containing therapy showed no such associations. Correlations with the level of circulating myeloid cells were also found. Considering these results for peripheral blood, T cells and myeloid cells were then investigated in the tumour mass for their relevance to patient outcome. The results of this study showed that patients with higher levels of intra-tumoural T cells were clinically fitter and experienced longer breast cancer-specific survival. In contrast, high relative levels of granulocytic cells were found in patients with poorer clinical health. Collectively, the results of these studies show that immune alterations in the blood and tumours of breast cancer patients may be used to gain insight into new prognostic biomarkers that could assist in developing new immunotherapies for this disease.

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