Novel strategies for enhancing immune responses to tumour associated antigens

Scourfield, David 2025. Novel strategies for enhancing immune responses to tumour associated antigens. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Background Tumour associated antigens (TAAs), such as the oncofoetal antigen 5T4, represent attractive targets for immunotherapies. In addition to directly targeting antigen, efforts have been made to improve the immunogenicity of 5T4 through vaccination. However, T cell recognition of TAAs is suboptimal as thymic selection removes high affinity, self-reactive T cell receptors (TCRs) from the repertoire. Modification of epitope peptide flanking residues (PFRs) within human leukocyte antigen class II (HLA-II) molecules can enhance anti-viral CD4+ T cell responses. Given the important role CD4+ T cells play in anti-tumour immunity, improving the immunogenicity of TAAs by this approach, through the generation of “neo” modified epitopes, may better inform future cancer vaccine design. In this study, novel strategies for targeting 5T4 to improve anti-tumour immune responses were explored. Results Initially, this study utilised phage display to try and identify high affinity peptide ligands to 5T4 for the development of novel immunotherapies. Despite evidence of sequence enrichment, synthesised peptides were unable to bind 5T4. Consequently, the focus shifted towards enhancing CD4+ T cell recognition of 5T4 through modulating PFRs. Combinatorial peptide libraries identified PFR substitutions that significantly increased the activation of a 5T4-specific CD4+ T cell clone. PFR neo-modifications could be combined to further improve antigen recognition, driven by increased avidity between HLA-II and TCR. In addition, structural definition of five 5T4 pHLA-DR1 complexes has identified new targets to explore this concept. Evidence with another TAA, DNAJB7, highlights the broader applicability of this approach to overcome tolerance in patients. Conclusions Current phage display libraries may not be suitable for identifying 5T4-binding peptides. PFR neo-modification is a promising strategy to enhance CD4⁺ T cell responses to TAAs. These findings support future studies to evaluate the efficacy of PFR neo-modified vaccines to inhibit tumour growth. Improving immunogenicity to 5T4 may provide benefit to patients of multiple tumours, including mesothelioma.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	22 May 2026
Last Modified:	22 May 2026 11:42
URI:	https://orca.cardiff.ac.uk/id/eprint/187171

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