Induction of proapoptotic antibodies to triple-negative breast cancer by vaccination with TRAIL death receptor DR5 DNA.

Abstract

TNF-related apoptosis-inducing ligand receptor 2 [TRAIL-R2 or death receptor 5 (DR5)] is expressed at elevated levels in a broad range of solid tumors to mediate apoptotic signals from TRAIL or agonist antibodies. We tested the hypothesis that DR5 DNA vaccination will induce proapoptotic antibody to trigger apoptosis of tumor cells. BALB/c mice were electrovaccinated with DNA-encoding wild-type human DR5 (phDR5) or its derivatives. Resulting immune serum or purified immune IgG induced apoptosis in triple-negative breast cancer (TNBC) cells, which were also TRAIL sensitive. The proapoptotic activity of immune serum at dilutions of 0.5-2% was comparable to that of 1-2 μg/ml of TRAIL. Apoptotic activity of immune serum was enhanced by antibody crosslinking. Apoptotic cell death induced by anti-DR5 antibody was shown by the cleavage of PARP and caspase-3. In contrast, immune serum had no effect on the proliferation of activated human T cells, which expressed low levels of DR5. In vivo, hDR5 reactive immune serum prevented growth of SUM159 TNBC cells in severe combined immune-deficient mice. DR5-specific IFN-γ-secreting T cells were also induced by DNA vaccination. Furthermore, the feasibility to overcome immune tolerance to self DR5 was shown by the induction of mouse DR5-binding antibody after electrovaccination of BALB/c mice with pmDR5ectm-Td1 encoding a fusion protein of mouse DR5 and an immunogenic fragment of tetanus toxin. These findings support DR5 as a promising vaccine target for controlling TNBC and other DR5-positive cancers.

• Authors: Marie P Piechocki, Gen Sheng Wu, Richard F Jones, Jennifer B Jacob, Heather Gibson, Stephen P Ethier, Judith Abrams, Hideo Yagita, K Venuprasad, Wei-Zen Wei
• Journal: International journal of cancer (Int J Cancer) Vol. 131 Issue 11 Pg. 2562-72 (Dec 01 2012) ISSN: 1097-0215 [Electronic] United States
• PMID: 22419388 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2012 UICC.

Chemical References

• Antibodies, Neoplasm
• Cancer Vaccines
• Immune Sera
• Immunoglobulin G
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Vaccines, DNA
• Interferon-gamma

Topics

• Animals
• Antibodies, Neoplasm (biosynthesis, immunology)
• Apoptosis (genetics, immunology)
• BALB 3T3 Cells
• Breast Neoplasms (genetics, immunology, therapy)
• Cancer Vaccines (administration & dosage, genetics, immunology)
• Cell Growth Processes (immunology)
• Cell Line, Tumor
• Female
• Humans
• Immune Sera (immunology)
• Immunoglobulin G (immunology)
• Interferon-gamma (immunology)
• Mice
• Mice, SCID
• NIH 3T3 Cells
• Receptors, TNF-Related Apoptosis-Inducing Ligand (genetics, immunology)
• T-Lymphocytes (immunology)
• Vaccines, DNA (administration & dosage, genetics, immunology)