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Title: Characterisation of CMV CD8+T-cell memory-inflation to immediate early HLA-C restricted targets and the potential of CMV as a vaccine vector for cancer therapy
Author: Hosie, Louise Christine
ISNI:       0000 0004 6346 9228
Awarding Body: University of Birmingham
Current Institution: University of Birmingham
Date of Award: 2017
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CMV CD8+T-cell memory-inflation can occupy up to 50% of the total CD8+ T cell pool. Studies using an MHC class I immunevasion-deleted strain revealed novel peptide-epitopes across the virus genome both in-frame and translated in a non-canonical manner. This study functionally and phenotypically characterised CD8+T-cells responding to these CMV-derived epitopes with age. They were found to be frequent component of the in vivo repertoire dedicated towards HCMV during latency. A HLA-Cw*0702-restricted immunodominant CD8+T-cell response that accumulated within elderly donors was identified to reach 32% of the total CD8+T-cell pool producing IFN-γ/TNF-α. Subsequently, HLA-Cw*0702-restricted memory-inflation was observed to a further two peptides dominating the CD8+T-cell memory compartment. HLA-Cw*0702 CD8+T-cells demonstrated a TEMRA phenotype - CD45RA+/CD27-/CD28-/CCR7-/perforinhigh/granzymeBhigh - and represented promising candidates for inclusion in HSCT adoptive immunotherapies. Consequently, the global HCMV-specific CD8+T-cell response is being vastly underestimated by restricting studies to; in-frame translation products, HLA-A/-B-restricted peptide-epitopes and utilising WT-strains to characterise novel CD8+T-cell targets. Lastly, understanding why particular HCMV antigens induce inflationary CD8+T-cells will facilitate harnessing HCMV as a cancer therapy. In an attempt to direct HCMV-mediated inflationary responses towards malignancies, a HCMV-based vaccine vector expressing the NYESO1 CTAg was generated. Preliminary results indicate the immunogenicity of such a vaccine in vitro.
Supervisor: Not available Sponsor: Medical Research Council (MRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QH301 Biology ; QH426 Genetics ; RC0254 Neoplasms. Tumors. Oncology (including Cancer)