title: Concomitant tumor and autoantigen vaccination supports renal cell carcinoma rejection.
abstract: Efficient tumor vaccination frequently requires adjuvant. Concomitant induction of an autoimmune response is discussed as a means to strengthen a weak tumor Ag-specific response. We asked whether the efficacy of dendritic cell (DC) vaccination with the renal cell carcinoma Ags MAGE-A9 (MAGE9) and G250 could be strengthened by covaccination with the renal cell carcinoma autoantigen GOLGA4. BALB/c mice were vaccinated with DC loaded with MHC class I-binding peptides of MAGE9 or G250 or tumor lysate, which sufficed for rejection of low-dose RENCA-MAGE9 and RENCA-G250 tumor grafts, but only retarded tumor growth at 200 times the tumor dose at which 100% of animals will develop a tumor. Instead, 75-100% of mice prevaccinated concomitantly with Salmonella typhimurium transformed with GOLGA4 cDNA in a eukaryotic expression vector rejected 200 times the tumor dose at which 100% of animals will develop tumor. In a therapeutic setting, the survival rate increased from 20-40% by covaccination with S. typhimurium-GOLGA4. Autoantigen covaccination significantly strengthened tumor Ag-specific CD4(+) and CD8(+) T cell expansion, particularly in peptide-loaded DC-vaccinated mice. Covaccination was accompanied by an increase in inflammatory cytokines, boosted IL-12 and IFN-gamma expression, and promoted a high tumor Ag-specific CTL response. Concomitant autoantigen vaccination also supported CCR6, CXCR3, and CXCR4 upregulation and T cell recruitment into the tumor. It did not affect regulatory T cells, but slightly increased myeloid-derived suppressor cells. Thus, tumor cell eradication was efficiently strengthened by concomitant induction of an immune response against a tumor Ag and an autoantigen expressed by the tumor cell. Activation of autoantigen-specific Th cells strongly supports tumor-specific Th cells and thereby CTL activation.
authors.affiliation: Department of Tumor Cell Biology, University Hospital of Surgery, University of Heidelberg, Germany.
authors.forename: Nicolás
authors.initials: N
authors.lastname: Herbert
authors.forename: Axel
authors.initials: A
authors.lastname: Haferkamp
authors.forename: Hubertus F
authors.initials: HF
authors.lastname: Schmitz-Winnenthal
authors.forename: Margot
authors.initials: M
authors.lastname: Zöller
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D001324:Autoantigens / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000235:genetics / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D007680:Kidney Neoplasms / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology; D054399:Receptors, CCR6 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D012486:Salmonella typhimurium / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014162:Transfection; D014611:Vaccination / Q000379:methods; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D001324:Autoantigens; C498126:CCR6 protein, mouse; D019496:Cancer Vaccines; C098772:GOLGA4 protein, human; C520253:MAGEA9 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D054399:Receptors, CCR6; D019707:Receptors, Chemokine; D022223:Vaccines, Subunit; D018664:Interleukin-12; D007371:Interferon-gamma; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases