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Title: Investigating the potential of the Metastasis Associated Antigen 1 (MTA1) for cancer immunotherapy in a murine model
Author: Assudani, Deepak
ISNI:       0000 0001 3431 1593
Awarding Body: Nottingham Trent University
Current Institution: Nottingham Trent University
Date of Award: 2007
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Immunotherapeutic approaches to target antigens associated with metastasis could provide a valuable means of targeting metastatic cells specifically. Metastasis Associated Antigen (MTA1) is one such relatively novel antigen, which has been associated with aggressive tumours, and shown to be over expressed in breast, oesophageal, colorectal, gastric and pancreatic cancer, amongst others. Various studies have indicated that MTA1 is essential for the transformation of cells and hence targeting it is unlikely to generate antigen loss variants. This study proposed to investigate MTA1 as a potential target for immunotherapy in a murine tumour model. We have shown that murine MTA1 (mMTA1) mRNA is highly expressed in most of the tumour cell lines as compared to normal tissues, which express mMTA1 at very low levels. Furthermore, to rule out any post-transcriptional modifications, MTA1 protein levels were also confirmed by western blotting. It was observed that most of the cell lines expressed MTA1 at high levels, whereas no protein expression was detected in the normal tissues by western blotting. Next, we decided to identify MHC class I and II restricted immunogenic peptides from murine and human MTA1 gene for syngeneic and transgenic mice respectively. Three MHC class I immunogenic peptides for Balb/c mice and two for C57BL/6 syngeneic mice were identified but none of those peptides were found to be naturally processed. Similarly, HLA-A2 and HLA-DR4 restricted immunogenic peptides were also identified using transgenic mice, but proved to be not endogenously processed. We hypothesised that, MTA1 being a ubiquitously expressed self-antigen, central and peripheral tolerance mechanisms might have a vital role in non-availability of high affinity T cell repertoire against MTA1 and therefore peptide vaccination might be unable to break tolerance to mMTA1 on its own. Hence we decided to investigate more potent strategies such as DNA vaccination, viral vaccination and xenogeneic vaccination to overcome this issue. Syngeneic or xenogeneic plasmid DNA vaccination was unable to generate an immune response to MTA1 in a mouse tumour model, even in combination with low dose cyclophosphamide for regulatory T cell depletion. Finally, semliki forest virus particles encoding for MTA1 did suggest weak immune reactivity against MTA1, as seen by delay in tumour growth in immunised animals. Further work will have to be done to optimise vaccination protocol to generate immune reaction against MTA1 and other such 'self-antigens'. Moreover, recent studies have suggested a presence of Treg repertoire against such SEREX defined self-antigens and immunisation with such antigens may actually be immunosuppressive. Such a possibility might exist for MTA1 and needs to be investigated.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available