Cancer Immunology, Immunotherapy

, Volume 61, Issue 7, pp 1005–1018

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

  • Fernanda V. Castro
  • Mariam Al-Muftah
  • Kate Mulryan
  • Hui-Rong Jiang
  • Jan-Wouter Drijfhout
  • Sumia Ali
  • Andrzej J. Rutkowski
  • Milena Kalaitsidou
  • David E. Gilham
  • Peter L. Stern
Original Article

DOI: 10.1007/s00262-011-1167-3

Cite this article as:
Castro, F.V., Al-Muftah, M., Mulryan, K. et al. Cancer Immunol Immunother (2012) 61: 1005. doi:10.1007/s00262-011-1167-3

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.

Keywords

5T4 oncofoetal antigen T cell repertoire T cell epitopes T regulatory cells Vaccine Immunotherapy 

Abbreviations

FR4

Folate Receptor 4

TAA

Tumour-associated antigens

Treg

T regulatory cell

mAb

Monoclonal antibody

IL

Interleukin

TCR

T cell Receptor

sc

Subcutaneous

im

Intramuscular

iv

Intravenous

CTLA-4

CTL-associated antigen-4

GITR

Glucocorticoid-induced TNF receptor

MLR

Mixed leucocyte reaction

Tc17

IL-17-producing CD8 T cell

CEA

Carcinoembryonic antigen

IDO

Indoleamine 2, 3-dioxygenase

CDR

Complementary determining region

Supplementary material

262_2011_1167_MOESM1_ESM.pdf (129 kb)
Supplementary material 1 (PDF 128 kb)

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Fernanda V. Castro
    • 1
  • Mariam Al-Muftah
    • 1
    • 4
  • Kate Mulryan
    • 1
  • Hui-Rong Jiang
    • 1
    • 2
  • Jan-Wouter Drijfhout
    • 3
  • Sumia Ali
    • 1
  • Andrzej J. Rutkowski
    • 1
  • Milena Kalaitsidou
    • 1
  • David E. Gilham
    • 4
  • Peter L. Stern
    • 1
  1. 1.Immunology Group, Paterson Institute for Cancer ResearchUniversity of ManchesterWithington, ManchesterUK
  2. 2.Strathclyde Institute of Pharmacy and Biomedical SciencesUniversity of StrathclydeGlasgowUK
  3. 3.Immunohaematology and Blood TransfusionLeiden University Medical CenterLeidenThe Netherlands
  4. 4.Clinical and Experimental Immunotherapy, Medical Oncology, School of Cancer and Enabling SciencesUniversity of Manchester, Manchester Academic Healthcare Science CentreManchesterUK

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