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Title: An in vitro study into the immune-phenotype of tumour cells following culture with gemcitabine
Author: Gravett, Andrew Michael
ISNI:       0000 0004 6349 7923
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2017
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In addition to slowing tumour growth, some chemotherapeutics have shown a remarkable capacity to modulate the immune response. One such chemotherapy is the anti-metabolite, gemcitabine (GEM). GEM has been shown to influence the quantity and activation of certain immune cell subsets when used in vivo. It has also been demonstrated that administration of GEM in conjunction with immunotherapy, such as dendritic cell vaccination, is beneficial in terms of overall survival and progression-free survival. By testing a panel of chemotherapeutic drugs in the present study it was found that GEM may alter the recognition and sensitivity of tumour cells to immune-mediated apoptosis. In vitro culture with GEM was shown to enhance expression of human leukocyte antigen (HLA) class I and CD95, cell surface molecules important for the efficient surveillance and effector function of the immune system. The HLA class I increase was beta-2-microglobulin dependent and changes may be underpinned by ERK, JNK and RelB-NFkB signalling pathways. Furthermore, culture with GEM induced immunoproteasomal components LMP2 and MECL-1 in tumour cells and, subsequently, the peptide antigen repertoire displayed on HLA class I was altered. These changes consisted of amino acid anchor-residue modifications which rendered the peptides likely to favour alternative HLA-allotypes and increased their predicted immunogenicity. The changes to the peptidome displayed by HLA class I may reveal sub-dominant immunogens to T-cells. These data may explain observations made in previous in vivo studies, advise as to which novel antigens could be utilised in future vaccination protocols and lend further credence to the idea that chemotherapy and immunotherapy could be used in combination.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available