Regulation of autologous immunity to the mouse 5T4 oncofoetal antigen: implications for immunotherapy.
AuthorsCastro, Fernanda V
Drijfhout, Jan W
Rutkowski, Andrzej J
Gilham, David E
Stern, Peter L
AffiliationImmunology Group, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Withington, Manchester, M20 4BX, UK.
MetadataShow full item record
AbstractEffective 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.
CitationRegulation of autologous immunity to the mouse 5T4 oncofoetal antigen: implications for immunotherapy. 2011: Cancer Immunol Immunother
JournalCancer Immunology Immunotherapy
- Immunotherapy success in prophylaxis cannot predict therapy: prime-boost vaccination against the 5T4 oncofoetal antigen.
- Authors: Ali S, Mulryan K, Taher T, Stern PL
- Issue date: 2007 Feb
- Regulatory T-cell depletion synergizes with gp96-mediated cellular responses and antitumor activity.
- Authors: Yan X, Zhang X, Wang Y, Li X, Wang S, Zhao B, Li Y, Ju Y, Chen L, Liu W, Meng S
- Issue date: 2011 Dec
- Active treatment of murine tumors with a highly attenuated vaccinia virus expressing the tumor associated antigen 5T4 (TroVax) is CD4+ T cell dependent and antibody mediated.
- Authors: Harrop R, Ryan MG, Myers KA, Redchenko I, Kingsman SM, Carroll MW
- Issue date: 2006 Sep
- Murine responses to recombinant MVA versus ALVAC vaccines against tumor-associated antigens, gp100 and 5T4.
- Authors: Hanwell DG, McNeil B, Visan L, Rodrigues L, Dunn P, Shewen PE, Macallum GE, Turner PV, Vogel TU
- Issue date: 2013 May
- Antigen-specific tumor vaccines. Development and characterization of recombinant adenoviruses encoding MART1 or gp100 for cancer therapy.
- Authors: Zhai Y, Yang JC, Kawakami Y, Spiess P, Wadsworth SC, Cardoza LM, Couture LA, Smith AE, Rosenberg SA
- Issue date: 1996 Jan 15