title: Inhibition and promotion of tumor growth with adeno-associated virus carcinoembryonic antigen vaccine and Toll-like receptor agonists.
abstract: Carcinoembryonic antigen (CEA) is a cancer vaccines' target. Several features of recombinant adeno-associated virus (rAAV) are attractive for vaccine applications. Combining other viral vector vaccines with Toll-like receptor (TLR) agonists enhances antitumor immunity. Wild-type and CEA transgenic (Tg) mice were immunized with rAAV-expressing CEA, the TLR9 agonist, oligodinucleotide (ODN)1826 and the TLR7 agonist, imiquimod. Mice were challenged with MC38 colon tumor cells and MC38 cells expressing CEA. rAAV-CEA immunization combined with ODN1826 or imiquimod enhanced CEA-specific T-helper 1 immunity and protected against tumor challenge in wild-type but not in CEA-Tg mice. In contrast, immunization with rAAV-CEA in CEA-Tg mice could abrogate the antitumor effects of ODN1826 and promote tumor growth. Compared to wild-type, CEA-Tg mice were characterized by a greater myeloid suppressor cell and T-helper 2 response to TLR agonists and to syngeneic tumors. Depleting PDCA1(+) plasmacytoid dendritic cells and Gr1(+) myeloid cells increased anti-CEA immune responses in CEA-Tg mice to rAAV-CEA-ODN1826 immunization, whereas depleting CD25(+) T cells did not. There are differences in the response of wild-type and CEA-Tg mice to rAAV-CEA, TLR agonists and syngeneic tumor. In CEA-Tg mice, tumor growth can be promoted with rAAV-CEA and TLR agonists. Dendritic and myeloid cells play a regulatory role.
authors.affiliation: Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. triozzp@ccf.org
authors.forename: P L
authors.initials: PL
authors.lastname: Triozzi
authors.forename: W
authors.initials: W
authors.lastname: Aldrich
authors.forename: S
authors.initials: S
authors.lastname: Ponnazhagan
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000628:therapy*; D003713:Dendritic Cells / Q000276:immunology; D000229:Dependovirus; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D000077271:Imiquimod; D008562:Membrane Glycoproteins / Q000819:agonists*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009838:Oligodeoxyribonucleotides / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D051217:Toll-Like Receptor 9 / Q000819:agonists*; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use
chemical_list: D000634:Aminoquinolines; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D014614:Vaccines, Synthetic; D000077271:Imiquimod