title: Solid tumor-targeted infiltrating cytotoxic T lymphocytes retained by a superantigen fusion protein.
abstract: Successful immune-mediated regression of solid tumors is difficult because of the small number of cytotoxic T lymphocytes (CTLs) that were traffic to the tumor site. Here, the targeting of tumor-specific infiltrating CTLs was dependent on a fusion protein consisting of human epidermal growth factor (EGF) and staphylococcal enterotoxin A (SEA) with the D227A mutation. EGF-SEA strongly restrained the growth of murine solid sarcoma 180 (S180) tumors (control versus EGF-SEA, mean tumor weight: 1.013 versus 0.197 g, difference  = 0.816 g). In mice treated with EGF-SEA, CD4+, CD8+ and SEA-reactive T lymphocytes were enriched around the EGFR expressing tumor cells. The EGF receptors were potentially phosphorylated by EGF-SEA stimulation and the fusion protein promoted T cells to release the tumoricidal cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). Intratumoral CTLs secreted cytolytic pore-forming perforins and granzyme B proteins near the surface of carcinomas, causing the death of many tumor cells. We additionally show that labeled EGF-SEA was directly targeted to the tumor tissue after intravenous (i.v.) injection. The findings demonstrate that antibody-like EGF-SEA plays an important role in arresting CTLs in the solid tumor site and has therapeutic potential as a tumor-targeting agent.
authors.affiliation: Key Laboratory of Industrial Microbiology, Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, People's Republic of China. jialinsun@tust.edu.cn
authors.forename: Jialin
authors.initials: J
authors.lastname: Sun
authors.forename: Lina
authors.initials: L
authors.lastname: Zhao
authors.forename: Lijie
authors.initials: L
authors.lastname: Teng
authors.forename: Feng
authors.initials: F
authors.lastname: Lin
authors.forename: Hongna
authors.initials: H
authors.lastname: Zhang
authors.forename: Zhengnan
authors.initials: Z
authors.lastname: Li
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gao
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology / Q000502:physiology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004768:Enterotoxins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology / Q000276:immunology* / Q000502:physiology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D020125:Mutation, Missense; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000502:physiology; D018089:Superantigens / Q000737:chemistry / Q000276:immunology / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology* / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use
chemical_list: D004768:Enterotoxins; D011993:Recombinant Fusion Proteins; D018089:Superantigens; D014409:Tumor Necrosis Factor-alpha