title: A vaccine that co-targets tumor cells and cancer associated fibroblasts results in enhanced antitumor activity by inducing antigen spreading.
abstract: Dendritic cell (DC) vaccines targeting only cancer cells have produced limited antitumor activity in most clinical studies. Targeting cancer-associated fibroblasts (CAFs) in addition to cancer cells may enhance antitumor effects, since CAFs, the central component of the tumor stroma, directly support tumor growth and contribute to the immunosuppressive tumor microenvironment. To co-target CAFs and tumor cells we developed a new compound DC vaccine that encodes an A20-specific shRNA to enhance DC function, and targets fibroblast activation protein (FAP) expressed in CAFs and the tumor antigen tyrosine-related protein (TRP)2 (DC-shA20-FAP-TRP2). DC-shA20-FAP-TRP2 vaccination induced robust FAP- and TRP2-specific T-cell responses, resulting in greater antitumor activity in the B16 melanoma model in comparison to monovalent vaccines or a vaccine encoding antigens and a control shRNA. DC-shA20-FAP-TRP2 vaccination enhanced tumor infiltration of CD8-positive T cells, and induced antigen-spreading resulting in potent antitumor activity. Thus, co-targeting of tumor cells and CAFs results in the induction of broad-based tumor-specific T-cell responses and has the potential to improve current vaccine approaches for cancer.
authors.affiliation: Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, Texas, United States of America ; Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, United States of America ; Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, United States of America ; Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America ; Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Stephen
authors.initials: S
authors.lastname: Gottschalk
authors.affiliation: Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Feng
authors.initials: F
authors.lastname: Yu
authors.affiliation: Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Minjun
authors.initials: M
authors.lastname: Ji
authors.affiliation: Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, Texas, United States of America ; Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Sunitha
authors.initials: S
authors.lastname: Kakarla
authors.affiliation: Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, Texas, United States of America ; Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Xiao-Tong
authors.initials: XT
authors.lastname: Song
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D010450:Endopeptidases; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism; D018093:Gelatinases / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008546:Melanoma, Experimental; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics / Q000276:immunology; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha; C500290:peptide SVYDFFVWL