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

Research output: Contribution to journalArticle

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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.
LanguageEnglish
Pages1005-1018
Number of pages14
JournalCancer Immunology, Immunotherapy
Volume61
Issue number7
DOIs
Publication statusPublished - 2012

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Immunotherapy
Immunity
Interleukin-17
T-Lymphocytes
Neoplasm Antigens
Adenoviridae
Folic Acid
Knockout Mice
Vaccination
T-Lymphocyte Epitopes
Antibodies
T-Lymphocyte Subsets
Regulatory T-Lymphocytes
Mouse Tpbg protein
Interleukin-10
Melanoma
Neoplasms
Glycoproteins
Vaccines
Therapeutics

Keywords

  • T regulatory cells
  • immunogenicity
  • tumour-associated antigens

Cite this

Castro, Fernanda V ; Al-Muftah, Mariam ; Mulryan, Kate ; Jiang, Hui-Rong ; Drijfhout, Jan-Wouter ; Ali, Sumia ; Rutkowski, Andrzej J ; Kalaitsidou, Milena ; Gilham, David E ; Stern, Peter L. / Regulation of autologous immunity to the mouse 5T4 oncofoetal antigen : implications for immunotherapy. In: Cancer Immunology, Immunotherapy. 2012 ; Vol. 61, No. 7. pp. 1005-1018.
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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.",
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Castro, FV, Al-Muftah, M, Mulryan, K, Jiang, H-R, Drijfhout, J-W, Ali, S, Rutkowski, AJ, Kalaitsidou, M, Gilham, DE & Stern, PL 2012, 'Regulation of autologous immunity to the mouse 5T4 oncofoetal antigen: implications for immunotherapy' Cancer Immunology, Immunotherapy, vol. 61, no. 7, pp. 1005-1018. https://doi.org/10.1007/s00262-011-1167-3

Regulation of autologous immunity to the mouse 5T4 oncofoetal antigen : implications for immunotherapy. / Castro, Fernanda V; Al-Muftah, Mariam; Mulryan, Kate; Jiang, Hui-Rong; Drijfhout, Jan-Wouter; Ali, Sumia; Rutkowski, Andrzej J; Kalaitsidou, Milena; Gilham, David E; Stern, Peter L.

In: Cancer Immunology, Immunotherapy, Vol. 61, No. 7, 2012, p. 1005-1018.

Research output: Contribution to journalArticle

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T1 - Regulation of autologous immunity to the mouse 5T4 oncofoetal antigen

T2 - Cancer Immunology, Immunotherapy

AU - Castro, Fernanda V

AU - Al-Muftah, Mariam

AU - Mulryan, Kate

AU - Jiang, Hui-Rong

AU - Drijfhout, Jan-Wouter

AU - Ali, Sumia

AU - Rutkowski, Andrzej J

AU - Kalaitsidou, Milena

AU - Gilham, David E

AU - Stern, Peter L

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