title: Development of a Listeria monocytogenes-based vaccine against hepatocellular carcinoma.
abstract: Live attenuated Listeria monocytogenes (LM) is a promising bacterial vector able to induce a T-cell response to tumor-associated antigens and demonstrates great potential for use in vaccine development. A novel recombinant LM-based vaccine (Lmdd (LM ΔdalΔdat)-MPFG (multiple peptide fusing genes)) was developed with the ability to express and secrete hepatocellular carcinoma (HCC)-related tumor-associated antigens fragments due to the insertion of hepatitis B virus (HBV)-X protein (HBx)-derived epitopes HBx(52-60) and HBx(140-148), the universal T-helper epitope, alpha-fetoprotein (AFP) epitope AFP(158-166), and melanoma antigen gene (MAGE)-3(271-279) into the HBV core protein. Following immunization with the Lmdd-MPFG vaccine, macrophages exhibited uptake of the bacteria; the vaccine was then nearly cleared 3 days after the first administration. It disappeared even more quickly following subsequent vaccinations. However, recombinant Lmdd-MPFG allowed for the full development of an antitumor response towards the human leukocyte antigen (HLA)-A0201 epitopes of MPFG. Each epitope stimulated an augmented T-cell proliferation and enhanced the supernatant level of interferon (IFN)-γ in vitro. In addition, IFN-γ-producing CD8(+) T cells as well as in vivo cytolytic activity were significantly increased in HLA-A2 transgenic mice. Additionally, the Lmdd-MPFG developed a strong antitumor response, as indicated by the significant resistance of immunized mice to MPFG-positive Hepa1-6 cell challenge in both a prophylactic and therapeutic setting. Tumor regression was accompanied by an enhanced cytotoxic T lymphocyte response and a decrease of regulatory T cells in the tumor. Collectively, these results suggest that utilizing attenuated LM as a vaccine vector, able to carry the MPFG gene, presents a potentially feasible strategy for prevention of HCC.
authors.affiliation: Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: D
authors.initials: D
authors.lastname: Yang
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Gao
authors.forename: R
authors.initials: R
authors.lastname: Jiang
authors.forename: L
authors.initials: L
authors.lastname: Deng
authors.forename: F R
authors.initials: FR
authors.lastname: Frankel
authors.forename: B
authors.initials: B
authors.lastname: Sun
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D004274:DNA, Recombinant; D000939:Epitopes; D005240:Feasibility Studies; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008089:Listeria monocytogenes / Q000276:immunology*; D008113:Liver Neoplasms / Q000276:immunology / Q000628:therapy*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology; D015534:Trans-Activators / Q000276:immunology; D014183:Transplantation, Heterologous; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D004274:DNA, Recombinant; D000939:Epitopes; C573135:Lmdd-MPFG vaccine; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D007371:Interferon-gamma