Vaccination with cytoplasmic ErbB-2 DNA protects mice from mammary tumor growth without anti-ErbB-2 antibody.
Wild-type ErbB-2 (E2) positive D2F2/E2 tumors are rejected by active vaccination with ErbB-2 DNA. However, anti-ErbB-2 Ab response can cause cardiac toxicity or interfere with cellular immunity. It will be advantageous to induce only cellular immunity by active vaccination. A panel of E2 DNA vaccines were constructed, and their vaccination efficacy was ranked as E2 > tyrosine kinase-deficient ErbB-2 (E2A) > full-length ErbB-2 targeted to the cytoplasm (cytE2) > tyrosine kinase-deficient cytE2 (cytE2A). E2A is a tyrosine kinase-deficient mutant containing a single residue substitution. CytE2 or cytE2A encodes a full-length protein that is targeted to and rapidly degraded in the cytosol by the proteasomes. Covaccination with cytE2A and GM-CSF or IL-2 DNA resulted in equivalent anti-tumor activity as E2. However, anti-ErbB-2 Ab was induced by E2 or E2A, but not cytE2 or cytE2A. Therefore, cytE2A appears to induce anti-tumor immunity without an Ab response. ErbB-2-specific CTL were detected in mice immunized with cytE2A and GM-CSF and have rejected tumor challenge. Depletion of CD8, but not CD4 T cells reduced anti-tumor immunity, indicating CTL as the effector cells. Covaccination with E2A and cytE2A induced synergistic anti-tumor activity, supporting enhanced peptide presentation from cytE2A, which was further evidenced by superior CTL activation using APCs expressing cytE2 vs E2. Taken together, cytoplasmic ErbB-2 DNA induced anti-tumor CTL, but not humoral response, demonstrating the feasibility of eliciting individual effector mechanism by targeted DNA vaccine.
Pilon
S A
SA
Department of Immunology and Microbiology, and Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA.
Piechocki
M P
MP
Wei
W Z
WZ
D000818:Animals; D000912:Antibodies, Neoplasm / Q000096:biosynthesis / Q000276:immunology*; D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology / Q000276:immunology; D004357:Drug Synergism; D005240:Feasibility Studies; D005260:Female; D018734:Genes, erbB-2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000378:metabolism; D009363:Neoplasm Proteins / Q000737:chemistry / Q000276:immunology / Q000502:physiology; D009368:Neoplasm Transplantation; D046988:Proteasome Endopeptidase Complex; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000276:immunology / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D000912:Antibodies, Neoplasm; D019496:Cancer Vaccines; D003546:Cysteine Endopeptidases; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007376:Interleukin-2; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D046988:Proteasome Endopeptidase Complex; D018719:Erb-b2 Receptor Tyrosine Kinases; D019444:Vaccines, DNA