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The nature of the human T cell response to the cancer antigen 5T4 is determined by the balance of regulatory and inflammatory T cells of the same antigen-specificity: implications for vaccine design

Besneux, Matthieu, Greenshields Watson, Alexander, Scurr, Martin, MacLachlan, Bruce, Christian, Adam, Davies, Michael, Hargest, Rachel, Phillips, Simon, Godkin, Andrew and Gallimore, Awen 2018. The nature of the human T cell response to the cancer antigen 5T4 is determined by the balance of regulatory and inflammatory T cells of the same antigen-specificity: implications for vaccine design. Cancer Immunology, Immunotherapy 10.1007/s00262-018-2266-1

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Abstract

The oncofoetal antigen 5T4 is a promising T cell target in the context of colorectal cancer, as demonstrated by a recent clinical study where 5T4-specific T cell responses, induced by vaccination or cyclophosphamide, were associated with a significantly prolonged survival of patients with metastatic disease. Whilst Th1-type (IFN-γ+) responses specific to 5T4, and other oncofoetal antigens, are often readily detectable in early stage CRC patients and healthy donors, their activity is suppressed as the cancer progresses by CD4+CD25hiFoxp3+ regulatory T cells (Treg) which contribute to the immunosuppressive environment conducive to tumour growth. This study mapped the fine specificity of Th1 and Treg cell responses to the 5T4 protein. Surprisingly, both immunogenic peptides and those recognised by Tregs clustered in the same HLA-DR transcending epitope-rich hotspots within the 5T4 protein. Similarly, regions of low Th1-cell immunogenicity also did not contain peptides capable of stimulating Tregs, further supporting the notion that Treg and Th1 cells recognise the same peptides. Understanding the rules which govern the balance of Th1 and Treg cells responding to a given peptide specificity is, therefore, of fundamental importance to designing strategies for manipulating the balance in favour of Th1 cells, and thus the most effective anti-cancer T cell responses.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Publisher: Springer
ISSN: 0340-7004
Date of First Compliant Deposit: 26 November 2018
Date of Acceptance: 19 October 2018
Last Modified: 29 Sep 2019 23:04
URI: http://orca.cf.ac.uk/id/eprint/117094

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