Peptide Vaccination Breaks Tolerance to HER-2/neu by Generating Vaccine-Specific FasL+ CD4+ T Cells: First Evidence for Intratumor Apoptotic Regulatory T Cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-04, Vol.70 (7), p.2686-2696
• Main Authors: GRITZAPIS, Angelos D, VOUTSAS, Loannis F, LEKKA, Eftychia, PAPAMICHAIL, Michael, BAXEVANIS, Constantin N
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antineoplastic agents; Apoptosis - immunology; Biological and medical sciences; Cancer Vaccines - immunology; Cancer Vaccines - pharmacology; CD8-Positive T-Lymphocytes - immunology; Fas Ligand Protein - immunology; Female; HLA-A2 Antigen - immunology; Lymphocytes, Tumor-Infiltrating - immunology; Male; Mammary Neoplasms, Experimental - immunology; Mammary Neoplasms, Experimental - prevention & control; Medical sciences; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Pharmacology. Drug treatments; Rats; Receptor, ErbB-2 - immunology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - pathology; Tumors; Vaccines, Subunit - immunology; Vaccines, Subunit - pharmacology
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-09-2517

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.