title: KBMA Listeria monocytogenes is an effective vector for DC-mediated induction of antitumor immunity.
abstract: Vaccine strategies that utilize human DCs to enhance antitumor immunity have yet to realize their full potential. Approaches that optimally target a spectrum of antigens to DCs are urgently needed. Here we report the development of a platform for loading DCs with antigen. It is based on killed but metabolically active (KBMA) recombinant Listeria monocytogenes and facilitates both antigen delivery and maturation of human DCs. Highly attenuated KBMA L. monocytogenes were engineered to express an epitope of the melanoma-associated antigen MelanA/Mart-1 that is recognized by human CD8+ T cells when presented by the MHC class I molecule HLA-A*0201. The engineered KBMA L. monocytogenes induced human DC upregulation of costimulatory molecules and secretion of pro-Th1 cytokines and type I interferons, leading to effective priming of Mart-1-specific human CD8+ T cells and lysis of patient-derived melanoma cells. KBMA L. monocytogenes expressing full-length NY-ESO-1 protein, another melanoma-associated antigen, delivered the antigen for presentation by MHC class I and class II molecules independent of the MHC haplotype of the DC donor. A mouse therapeutic tumor model was used to show that KBMA L. monocytogenes efficiently targeted APCs in vivo to induce protective antitumor responses. Together, our data demonstrate that KBMA L. monocytogenes may be a powerful platform that can both deliver recombinant antigen to DCs for presentation and provide a potent DC-maturation stimulus, making it a potential cancer vaccine candidate.
authors.affiliation: Cancer Institute, New York University School of Medicine, New York, New York 10016, USA. Mojcaskoberne@yahoo.de
authors.forename: Mojca
authors.initials: M
authors.lastname: Skoberne
authors.forename: Alice
authors.initials: A
authors.lastname: Yewdall
authors.forename: Keith S
authors.initials: KS
authors.lastname: Bahjat
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Godefroy
authors.forename: Peter
authors.initials: P
authors.lastname: Lauer
authors.forename: Edward
authors.initials: E
authors.lastname: Lemmens
authors.forename: Weiqun
authors.initials: W
authors.lastname: Liu
authors.forename: Will
authors.initials: W
authors.lastname: Luckett
authors.forename: Meredith
authors.initials: M
authors.lastname: Leong
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Dubensky
authors.forename: Dirk G
authors.initials: DG
authors.lastname: Brockstedt
authors.forename: Nina
authors.initials: N
authors.lastname: Bhardwaj
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology; D015789:HLA-A2 Antigen; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006801:Humans; D008089:Listeria monocytogenes / Q000235:genetics / Q000276:immunology*; D058965:MART-1 Antigen; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D016207:Cytokines; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D000949:Histocompatibility Antigens Class II; D058965:MART-1 Antigen; C548667:MLANA protein, human; C548668:Mlana protein, mouse; D009363:Neoplasm Proteins; D011994:Recombinant Proteins