Fusion protein vaccine by domains of bacterial exotoxin linked with a tumor antigen generates potent immunologic responses and antitumor effects.
Antigen-specific immunotherapy represents an attractive approach for cancer treatment because of the capacity to eradicate systemic tumors at multiple sites in the body while retaining the requisite specificity to discriminate between neoplastic and nonneoplastic cells. It has been shown that certain domains of bacterial exotoxins facilitate translocation from extracellular and vesicular compartments into the cytoplasm. This feature provides an opportunity to enhance class I and/or II presentation of exogenous antigen to T lymphocytes. We investigated previously whether the translocation domain (domain II) of Pseudomonas aeruginosa exotoxin A with a model tumor antigen, human papillomavirus type 16 E7, in the context of a DNA vaccine could enhance vaccine potency. We then attempted to determine whether this chimeric molecule could also generate strong antigen-specific immunologic responses and enhance the potency of cancer vaccine in the protein format. Our results show that vaccination with the PE(DeltaIII)-E7-KDEL3 fusion protein enhances MHC class I and II presentation of E7, leading to dramatic increases in the number of E7-specific CD8+ and CD4+ T-cell precursors and markedly raised titers of E7-specific antibodies. Furthermore, the PE(DeltaIII)-E7-KDEL3 protein generates potent antitumor effects against s.c. E7-expressing tumors and preestablished E7-expressing metastatic lung tumors. Further, mice immunized with PE(DeltaIII)-E7-KDEL3 protein vaccine also retained long-term immunologic responses and antitumor effects. Our results indicate that retrograde-fusion protein via the delivery domains of exotoxins with an antigen greatly enhances in vivo antigen-specific immunologic responses and represents a novel strategy to improve cancer vaccine potency.
Liao
Chao-Wei
CW
Animal Technology Institute Taiwan, Miaoli, Taiwan.
Chen
Chi-An
CA
Lee
Chien-Nan
CN
Su
Yi-Ning
YN
Chang
Ming-Cheng
MC
Syu
Ming-Houg
MH
Hsieh
Chang-Yao
CY
Cheng
Wen-Fang
WF
D036002:ADP Ribose Transferases / Q000235:genetics / Q000276:immunology*; D000818:Animals; D001427:Bacterial Toxins / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005098:Exotoxins / Q000235:genetics / Q000276:immunology*; D005260:Female; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D009842:Oligopeptides / Q000235:genetics / Q000276:immunology*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D021382:Protein Sorting Signals / Q000235:genetics; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology*; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D005098:Exotoxins; D009842:Oligopeptides; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D021382:Protein Sorting Signals; D011993:Recombinant Fusion Proteins; D014614:Vaccines, Synthetic; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C059731:oncogene protein E7, Human papillomavirus type 16; C073762:lysyl-aspartyl-glutamyl-leucine