Peptide vaccination breaks tolerance to HER-2/neu by generating vaccine-specific FasL(+) CD4(+) T cells: first evidence for intratumor apoptotic regulatory T cells

Cancer Res. 2010 Apr 1;70(7):2686-96. doi: 10.1158/0008-5472.CAN-09-2517. Epub 2010 Mar 16.

Abstract

BALB/c mice transgenic (Tg) for the transforming rat neu oncogene (BALB-neuT) are genetically predestined to develop mammary carcinogenesis in a process similar to that in humans. We crossed HLA-A2.1/HLA-DR1 (A2.1/DR1) Tg mice with BALB-neuT mice to generate A2.1/DR1 x BALB-neuT triple Tg (A2.1/DR1 x neuT(+)) mice, which represent an improvement over BALB-neuT mice for evaluating vaccination regimens to overcome tolerance against HER-2/neu. A vaccine formulation strategy, consisting of synthetic peptides from the rat HER-2/neu oncogene combined with granulocyte macrophage colony-stimulating factor, was highly effective in preventing the growth of established transplantable tumors in male A2.1/DR1 x neuT(+) mice. Vaccination with HER-2(435-443) (p435) CTL peptide alone induced weak antitumor responses, which were characterized by increased numbers of regulatory T cells (Treg) and low numbers of vaccine-specific CD8(+) CTL and helper T cells (Th). The administration of p435 plus HER-2(776-790) (p776; helper peptide) reversed this situation, inducing functionally active, peptide-specific CTL and Th. There was a striking change in the intratumoral balance of Tregs (decrease) and vaccine-specific Th (increase) that directly correlated with tumor rejection. Intratumoral administration of anti-FasL antibody promoted tumor growth. The decrease in Tregs (Fas(+)) was due to apoptosis induced by cell contact with Fas ligand(+) (L)(+) Th. Mice vaccinated with p435 plus p776 exhibited long-lasting antitumor immunity. Our vaccine regimen also significantly delayed the outgrowth of mammary carcinomas in female A2.1/DR1 x neuT(+) animals. We provide a mechanism to overcome tolerance against HER-2/neu, which proposes a combined vaccination with two (Th and CTL) HER-2 peptides against HER-2/neu-expressing tumors.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cancer Vaccines / immunology*
  • Cancer Vaccines / pharmacology
  • Fas Ligand Protein / immunology*
  • Female
  • HLA-A2 Antigen / immunology
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Male
  • Mammary Neoplasms, Experimental / immunology*
  • Mammary Neoplasms, Experimental / prevention & control*
  • Mice
  • Mice, Inbred BALB C
  • Molecular Sequence Data
  • Rats
  • Receptor, ErbB-2 / immunology*
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology
  • Vaccines, Subunit / immunology*
  • Vaccines, Subunit / pharmacology

Substances

  • Cancer Vaccines
  • Fas Ligand Protein
  • Fasl protein, mouse
  • HLA-A2 Antigen
  • Vaccines, Subunit
  • Receptor, ErbB-2