Targeted delivery of the ErbB2/HER2 tumor antigen to professional APCs results in effective antitumor immunity

TY - JOUR

T1 - Targeted delivery of the ErbB2/HER2 tumor antigen to professional APCs results in effective antitumor immunity

AU - Rohrbach, Florian

AU - Weth, Robert

AU - Kursar, Mischo

AU - Sloots, Arjen

AU - Mittrücker, Hans-Willi

AU - Wels, Winfried S

PY - 2005/5/1

Y1 - 2005/5/1

N2 - Activation of T cells by professional APCs that present peptide epitopes of tumor-associated Ags is critical for the induction of cell-mediated immunity against tumors. To facilitate targeted delivery of the ErbB2 (HER2, neu) tumor Ag to APCs in vivo, we have generated chimeric proteins that contain the extracellular domain of CTLA-4 for binding to B7 molecules on the APC surface, which is genetically fused to a human ErbB2 fragment as an antigenic determinant. Bacterially expressed CTLA-4-ErbB2 fusion protein and a similar molecule harboring in addition the translocation domain of Pseudomonas exotoxin A as an endosome escape function displayed specific binding to B7-expressing cells, followed by protein internalization and intracellular degradation. Vaccination of BALB/c mice with the fusion proteins resulted in the induction of ErbB2-specific CD8(+) T cells and CTL-dependent protection from subsequent challenge with ErbB2-expressing but not ErbB2-negative murine renal carcinoma cells. In a therapeutic setting, injection of CTLA-4-ErbB2 protein vaccines caused rejection of established ErbB2-expressing tumors. Thereby, immunological memory was induced, leading to long-term systemic immunity and protection against rechallenge several months later. Our results demonstrate that these chimeric protein vaccines are effective tools for the induction of ErbB2-specific, T cell-mediated immunity.

AB - Activation of T cells by professional APCs that present peptide epitopes of tumor-associated Ags is critical for the induction of cell-mediated immunity against tumors. To facilitate targeted delivery of the ErbB2 (HER2, neu) tumor Ag to APCs in vivo, we have generated chimeric proteins that contain the extracellular domain of CTLA-4 for binding to B7 molecules on the APC surface, which is genetically fused to a human ErbB2 fragment as an antigenic determinant. Bacterially expressed CTLA-4-ErbB2 fusion protein and a similar molecule harboring in addition the translocation domain of Pseudomonas exotoxin A as an endosome escape function displayed specific binding to B7-expressing cells, followed by protein internalization and intracellular degradation. Vaccination of BALB/c mice with the fusion proteins resulted in the induction of ErbB2-specific CD8(+) T cells and CTL-dependent protection from subsequent challenge with ErbB2-expressing but not ErbB2-negative murine renal carcinoma cells. In a therapeutic setting, injection of CTLA-4-ErbB2 protein vaccines caused rejection of established ErbB2-expressing tumors. Thereby, immunological memory was induced, leading to long-term systemic immunity and protection against rechallenge several months later. Our results demonstrate that these chimeric protein vaccines are effective tools for the induction of ErbB2-specific, T cell-mediated immunity.

KW - Animals

KW - Antigen Presentation

KW - Antigen-Presenting Cells

KW - Antigens, CD

KW - Antigens, Differentiation

KW - CD8-Positive T-Lymphocytes

KW - CTLA-4 Antigen

KW - Cancer Vaccines

KW - Carcinoma, Renal Cell

KW - Cell Line, Tumor

KW - Epitopes, T-Lymphocyte

KW - Escherichia coli

KW - Female

KW - Gene Expression Regulation, Bacterial

KW - Gene Expression Regulation, Neoplastic

KW - Gene Targeting

KW - Humans

KW - Lymphocyte Activation

KW - Mice

KW - Mice, Inbred BALB C

KW - Protein Binding

KW - Receptor, erbB-2

KW - Recombinant Fusion Proteins

KW - Vaccines, DNA

M3 - SCORING: Journal article

C2 - 15843546

VL - 174

SP - 5481

EP - 5489

JO - J IMMUNOL

JF - J IMMUNOL

SN - 0022-1767

IS - 9

ER -