Fusion protein vaccine by domains of bacterial exotoxin linked with a tumor antigen generates potent immunologic responses and antitumor effects
Journal
Cancer Research
Journal Volume
65
Journal Issue
19
Pages
9089-9098
Date Issued
2005
Author(s)
Abstract
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(ΔIII)-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(ΔIII)-E7- KDEL3 protein generates potent antitumor effects against s.c. E7-expressing tumors and pre-established E7-expressing metastatic lung tumors. Further, mice immunized with PE(ΔIII)-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. ?2005 American Association for Cancer Research.
SDGs
Other Subjects
cancer vaccine; DNA vaccine; exotoxin; hybrid protein; tumor antigen; animal cell; antibody specificity; antigen specificity; antineoplastic activity; article; cancer therapy; cell compartmentalization; female; glycosylation; immune response; immunotherapy; mouse; nonhuman; priority journal; protein domain; Pseudomonas aeruginosa; T lymphocyte activation; ADP Ribose Transferases; Animals; Bacterial Toxins; Cancer Vaccines; CD8-Positive T-Lymphocytes; Epitopes, T-Lymphocyte; Exotoxins; Female; Lung Neoplasms; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Oligopeptides; Oncogene Proteins, Viral; Protein Sorting Signals; Protein Structure, Tertiary; Recombinant Fusion Proteins; Vaccines, Synthetic; Virulence Factors
Type
journal article