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Identification of novel antigens for T cell targeting of prostate cancer stem cells

Codd, Amy 2019. Identification of novel antigens for T cell targeting of prostate cancer stem cells. PhD Thesis, Cardiff University.
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Cancer stem cells (CSC) are a subpopulation of tumour cells which are resistant to conventional therapy, such as radiation and chemotherapy, and contribute to tumour progression and relapse. We hypothesised that CSC could be specifically targeted by T cells, in an antigen specific manner. This was investigated in prostate cancer, because it is associated with a relapse rate of 15-40% and progressive disease has poor survival outcomes. The CSC markers, CD44 α2β1Integrin and CD133 and aldehyde dehydrogenase (ALDH), were compared to optimise CSC isolation in DU145 cells and primary prostate cancer cells. I did not identify a conclusive CD44+ CD49bhigh CD133+ population, in contrast to previous work on primary prostate cancer cells. ALDH high DU145 cells demonstrated higher clonogenicity and self-renewal in vitro and tumorigenicity in vivo, than ALDH low DU145 cells. In the DU145 and primary prostate cancer cells, the ALDH high population divided less than the ALDH low population. Gene expression analysis identified genes associated with cell cycling and NOTCH signalling differentially expressed in the ALDH high compared to the ALDH low DU145 and primary prostate cancer cells. I carried out HLA ligandome analysis of the DU145 cells to identify novel antigens. The ligandome dataset was analysed using in silico algorithms, PCR and homology modelling to identify therapeutically relevant CSC antigens. Candidate antigens identified include ARHGAP42, XPO1, RLN2 and AKT2, which were also expressed in the primary prostate cancer cells. In preliminary experiments, antigen specific T cell lines were found to produce cytokines in response to cells presenting the target antigen. This study demonstrated that CSC markers are of varying utility in identifying distinct populations. CSC characteristics were confirmed in prostate cancer cells identified by high ALDH activity. We conclude that prostate CSC are suitable targets for T cell immunotherapy, on the basis of presenting therapeutically relevant antigens.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Funders: Tenovus Cancer Care PhD Studentship
Date of First Compliant Deposit: 22 January 2020
Last Modified: 07 Jan 2022 02:35

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