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

Hosie, Louise (2017). 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. University of Birmingham. Ph.D.

[img] Hosie17PhD.pdf
PDF - Accepted Version
Restricted to Repository staff only until 21 October 2019.

Download (18MB) | Request a copy

Abstract

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.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
Supervisor(s):
Supervisor(s)EmailORCID
Moss, Paul A.UNSPECIFIEDUNSPECIFIED
Pachnio, AnnetteUNSPECIFIEDUNSPECIFIED
Licence:
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: Institute of Immunology and Immunotherapy
Funders: Medical Research Council
Subjects: Q Science > QH Natural history > QH301 Biology
Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
URI: http://etheses.bham.ac.uk/id/eprint/7410

Actions

Request a Correction Request a Correction
View Item View Item

Downloads

Downloads per month over past year