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Title: HAGE, a novel cancer/testis antigen with strong potential as a target for immunotherapy against cancers
Author: Mathieu, Morgan G.
ISNI:       0000 0001 3621 237X
Awarding Body: Nottingham Trent University
Current Institution: Nottingham Trent University
Date of Award: 2007
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Since van der Bruggen et al. (1991) first identified specific human tumour antigens of the MAGE family, numerous potential immunotherapeutic targets have been discovered, often belonging to the so-called cancer/testis (CT) gene family. In a search for novel epitopes from potential tumour target antigens, HAGE, a CT antigen, has been studied. It was first identified in a sarcoma and has since been reported in several carcinomas and leukaemias at the mRNA level only. This study proposed to investigate HAGE as a potential target for immunotherapy in a murine tumour model. HAGE mRNA was found to be expressed in a small proportion of carcinomas, some melanomas and in a strong proportion of chronic myeloid leukaemias as compared to normal tissues, which do not express HAGE with the exception of testis. HAGE protein levels were also confirmed on tissue sections and in cell lines in order to rule out any post-transcriptional modifications. Furthermore, HAGE has been previously described as member of the DEAD-box family of ATP-dependent RNA helicases but very little is known about its actual function. RNA helicases are involved in various steps of RNA metabolism and their over-expression has often been linked with tumorogenesis. Using a combination of silencing and transfection experiments, HAGE was proven to be critical for tumour cell proliferation. Next, the identification of candidate MHC class I and class II immunogenic peptides derived from the HAGE protein was undertaken by combining reverse immunology with the use of HLA transgenic mice. Four HLA-A2 peptides were found to be immunogenic in C57BL/6-HHDII mice with one of them being also naturally processed. Four HLA-DR1/-DR4 peptides were defined as immunogenic in FVB/N-DR1 and C57BL/6-DR4 mice with two of them being also endogenously processed. The discovery of three novel HAGE-derived epitopes may then contribute to the range of immunotherapeutic targets for use in cancer vaccination programs. Finally, potent DNA-based vaccination strategies targeting HAGE were evaluated in an in vivo tumour model developed in HHDII-DR1, double transgenic mice. HAGE DNA vaccination by either gene gun or intra-muscular injection led to tumour protection and/or clearance in immunised animals. Also, the use of co-stimulatory molecules to boost the immune response induced by HAGE DNA vaccination was studied in a therapeutic setup and B7.2 appeared to be the most promising one. However, further work is needed to improve this tumour model and assess other methods of vaccination such as syngeneic dendritic cell-based vaccination or viral vaccination and the use of Semliki Forest virus. Collectively, these data demonstrate that HAGE represents a valid candidate target for several cancers and should maybe be included in future immunotherapeutic design.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available