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    Regulation of autologous immunity to the mouse 5T4 oncofoetal antigen: implications for immunotherapy.

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    Authors
    Castro, Fernanda V
    Al-Muftah, Mariam
    Mulryan, Kate
    Jiang, Hui-Rong
    Drijfhout, Jan W
    Ali, Sumia
    Rutkowski, Andrzej J
    Kalaitsidou, Milena
    Gilham, David E
    Stern, Peter L
    Affiliation
    Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, UK.
    Issue Date
    2011-11-30
    
    Metadata
    Show full item record
    Abstract
    Effective vaccination against tumour-associated antigens (TAA) such as the 5T4 oncofoetal glycoprotein may be limited by the nature of the T cell repertoire and the influence of immunomodulatory factors in particular T regulatory cells (Treg). Here, we identified mouse 5T4-specific T cell epitopes using a 5T4 knock out (5T4KO) mouse and evaluated corresponding wild-type (WT) responses as a model to refine and improve immunogenicity. We have shown that 5T4KO mice vaccinated by replication defective adenovirus encoding mouse 5T4 (Adm5T4) generate potent 5T4-specific IFN-γ CD8 and CD4 T cell responses which mediate significant protection against 5T4 positive tumour challenge. 5T4KO CD8 but not CD4 primed T cells also produced IL-17. By contrast, Adm5T4-immunized WT mice showed no tumour protection consistent with only low avidity CD8 IFN-γ, no IL-17 T cell responses and no detectable CD4 T cell effectors producing IFN-γ or IL-17. Treatment with anti-folate receptor 4 (FR4) antibody significantly reduced the frequency of Tregs in WT mice and enhanced 5T4-specific IFN-γ but reduced IL-10 T cell responses but did not reveal IL-17-producing effectors. This altered balance of effectors by treatment with FR4 antibody after Adm5T4 vaccination provided modest protection against autologous B16m5T4 melanoma challenge. The efficacy of 5T4 and some other TAA vaccines may be limited by the combination of TAA-specific T regs, the deletion and/or alternative differentiation of CD4 T cells as well as the absence of distinct subsets of CD8 T cells.
    Citation
    Regulation of autologous immunity to the mouse 5T4 oncofoetal antigen: implications for immunotherapy. 2011: Cancer Immunol Immunother
    Journal
    Cancer Immunology Immunotherapy
    URI
    http://hdl.handle.net/10541/216270
    DOI
    10.1007/s00262-011-1167-3
    PubMed ID
    22127365
    Type
    Article
    Language
    en
    ISSN
    1432-0851
    ae974a485f413a2113503eed53cd6c53
    10.1007/s00262-011-1167-3
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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