TY - JOUR
T1 - 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
T2 - implications for vaccine design
AU - Besneux, Matthieu
AU - Greenshields-Watson, Alexander
AU - Scurr, Martin J.
AU - MacLachlan, Bruce J.
AU - Christian, Adam
AU - Davies, Michael M.
AU - Hargest, Rachel
AU - Phillips, Simon
AU - Godkin, Andrew
AU - Gallimore, Awen
PY - 2019/2/13
Y1 - 2019/2/13
N2 - 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 + CD25 hi Foxp3 + 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.
AB - 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 + CD25 hi Foxp3 + 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.
KW - 5T4
KW - Antigen specificity
KW - Cancer
KW - Regulatory T cells
KW - T cells
UR - http://www.scopus.com/inward/record.url?scp=85056353165&partnerID=8YFLogxK
U2 - 10.1007/s00262-018-2266-1
DO - 10.1007/s00262-018-2266-1
M3 - Article
C2 - 30406375
AN - SCOPUS:85056353165
VL - 68
SP - 247
EP - 256
JO - Cancer Immunology Immunotherapy
JF - Cancer Immunology Immunotherapy
SN - 0340-7004
IS - 2
ER -