Vaccination with an adenoviral vector encoding the tumor antigen directly linked to invariant chain induces potent CD4(+) T-cell-independent CD8(+) T-cell-mediated tumor control

Eur J Immunol. 2009 Oct;39(10):2725-36. doi: 10.1002/eji.200939543.

Abstract

Antigen-specific immunotherapy is an attractive strategy for cancer control. In the context of antiviral vaccines, adenoviral vectors have emerged as a favorable means for immunization. Therefore, we chose a strategy combining use of these vectors with another successful approach, namely linkage of the vaccine antigen to invariant chain (Ii). To evaluate this strategy we used a mouse model, in which an immunodominant epitope (GP33) of the LCMV glycoprotein (GP) represents the tumor-associated neoantigen. Prophylactic vaccination of C57BL/6 mice with a replication-deficient human adenovirus 5 vector encoding GP linked to Ii (Ad-Ii-GP) resulted in complete protection against GP33-expressing B16.F10 tumors. Therapeutic vaccination with Ad-Ii-GP delayed tumor growth by more than 2 wk compared with sham vaccination. Notably, therapeutic vaccination with the linked vaccine was significantly better than vaccination with adenovirus expressing GP alone (Ad-GP), or GP and Ii unlinked (Ad-GP+Ii). Ad-Ii-GP- induced tumor control depended on an improved generation of the tumor-associated neoantigen-specific CD8(+) T-cell response and was independent of CD4(+) T cells. IFN-gamma was shown to be a key player during the tumor degradation. Finally, Ad-Ii-GP but not Ad-GP vaccination can break the immunological non-reactivity in GP transgenic mice indicating that our vaccine strategy will prove efficient also against endogenous tumor antigens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics*
  • Animals
  • Antigens, Differentiation, B-Lymphocyte / genetics
  • Antigens, Differentiation, B-Lymphocyte / immunology*
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / immunology*
  • Antigens, Viral / genetics
  • Antigens, Viral / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cancer Vaccines / genetics
  • Cancer Vaccines / immunology*
  • Cancer Vaccines / therapeutic use
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects
  • Cytotoxicity, Immunologic / immunology
  • Genes, MHC Class II / genetics
  • Genetic Vectors / genetics*
  • Glycoproteins / genetics
  • Glycoproteins / immunology
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / immunology*
  • Humans
  • Interferon-gamma / metabolism
  • Interferon-gamma / pharmacology
  • Lymphocyte Activation / immunology
  • Lymphocyte Depletion
  • Lymphocytic Choriomeningitis / immunology
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / metabolism
  • Melanoma, Experimental / pathology
  • Melanoma, Experimental / prevention & control
  • Melanoma, Experimental / therapy
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Peptide Fragments / genetics
  • Peptide Fragments / immunology
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Spleen / cytology
  • Spleen / immunology
  • Survival Analysis
  • Vaccines, DNA / genetics
  • Vaccines, DNA / immunology
  • Vaccines, DNA / therapeutic use
  • Viral Envelope Proteins / genetics
  • Viral Envelope Proteins / immunology
  • Viral Proteins / genetics
  • Viral Proteins / immunology

Substances

  • Antigens, Differentiation, B-Lymphocyte
  • Antigens, Neoplasm
  • Antigens, Viral
  • Cancer Vaccines
  • Glycoproteins
  • Histocompatibility Antigens Class II
  • Peptide Fragments
  • Recombinant Fusion Proteins
  • Vaccines, DNA
  • Viral Envelope Proteins
  • Viral Proteins
  • glycoprotein C, lymphocytic choriomeningitis virus
  • glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus
  • invariant chain
  • Interferon-gamma