title: Cytotoxic T lymphocyte-dependent tumor growth inhibition by a vascular endothelial growth factor-superantigen conjugate.
abstract: T cells are major lymphocytes in the blood and passengers across the tumor vasculature. If these T cells are retained in the tumor site, a therapeutic potential will be gained by turning them into tumor-reactive cytotoxic T lymphocytes (CTLs). A fusion protein composed of human vascular endothelial growth factor (VEGF) and staphylococcal enterotoxin A (SEA) with a D227A mutation strongly repressed the growth of murine solid sarcoma 180 (S180) tumors (control versus VEGF-SEA treated with 15μg, mean tumor weight: 1.128g versus 0.252g, difference=0.876g). CD4(+) and CD8(+) T cells driven by VEGF-SEA were accumulated around VEGFR expressing tumor cells and the induced CTLs could release the tumoricidal cytokines, such as interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). Meanwhile, intratumoral CTLs secreted cytolytic pore-forming perforin and granzyme B proteins around tumor cells, leading to the death of tumor cells. The labeled fusion proteins were gradually targeted to the tumor site in an imaging mice model. These results show that VEGF-SEA can serve as a tumor targeting agent and sequester active infiltrating CTLs into the tumor site to kill tumor cells, and could therefore be a potential therapeutical drug for a variety of cancers.
authors.affiliation: Shanghai Chest Hospital, Shanghai 200433, PR China.
authors.forename: Qingwen
authors.initials: Q
authors.lastname: Sun
authors.forename: Songmin
authors.initials: S
authors.lastname: Jiang
authors.forename: Baohui
authors.initials: B
authors.lastname: Han
authors.forename: Tongwen
authors.initials: T
authors.lastname: Sun
authors.forename: Zhengnan
authors.initials: Z
authors.lastname: Li
authors.forename: Lina
authors.initials: L
authors.lastname: Zhao
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gao
authors.forename: Jialin
authors.initials: J
authors.lastname: Sun
mesh_terms: D000818:Animals; D003602:Cytotoxicity, Immunologic; D004768:Enterotoxins / Q000235:genetics / Q000627:therapeutic use*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D000922:Immunotoxins / Q000235:genetics / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009154:Mutation; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D012509:Sarcoma / Q000628:therapy*; D018089:Superantigens / Q000235:genetics / Q000627:therapeutic use*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000627:therapeutic use*
chemical_list: D004768:Enterotoxins; D000922:Immunotoxins; D011993:Recombinant Fusion Proteins; D018089:Superantigens; D042461:Vascular Endothelial Growth Factor A; C579137:human vascular endothelial growth factor-staphylococcal enterotoxin A fusion protein; C026066:enterotoxin A, Staphylococcal