title: Granulocyte-macrophage colony-stimulating factor gene-transduced tumor cells combined with tumor-derived gp96 inhibit tumor growth in mice.
abstract: Granulocyte-macrophage colony-stimulating factor (GM-CSF)-based cancer cell vaccines have been shown to be potent inducers of antitumor immunity in several murine models, but the antitumor effects on established tumors have been minimal. Conversely, the major role of the heat shock protein gp96, localized in the endoplasmic reticulum (ER), is to act as a molecular chaperone to assist the folding of nascent polypeptide chains in the ER. gp96 derived from tumor cells elicits specific protective immunity against parental tumors, presumably through the transport of tumor-specific peptides to antigen-presenting cells and the maturation of dendritic cells (DCs). However, the therapeutic effects of tumor-derived gp96 on established tumors have not been promising. The present study analyzes the therapeutic effects of GM-CSF gene-transduced Lewis lung cancer (LLC/GM) cells combined with LLC-derived gp96 on established wild-type LLC tumors in immunocompetent C57BL/6 mice. Therapy with either irradiated LLC/GM cells or LLC-derived gp96 barely affected established LLC tumor growth. The antitumor effect was significantly enhanced when 1 microg of LLC-derived gp96 was administered together with 1 x 10(6) irradiated LLC/GM cells (p < 0.05). The antitumor effects of irradiated LLC/GM cells and LLC-derived gp96 required mainly CD8(+) T cells. Spleen cells obtained from mice vaccinated with irradiated LLC/GM cells and LLC-derived gp96 showed specific CD8 cytotoxic activities against LLC cells (specific lysis rate of approximately 28%). This antibody response was not associated with a synergic effect of the combination therapy. Moreover, draining lymph nodes from mice immunized with irradiated LLC/GM cells and LLC-derived gp96 contained more migrating mature CD11c(+) cells (higher levels of CD86 and major histocompatibility complex [MHC] class II molecules) compared with those from any other immunization protocols. These results suggest that the combination of irradiated LLC/GM cells and tumor-derived gp96 has potential as a new immunogene therapeutic strategy against lung cancer.
authors.affiliation: First Department of Medicine, Hokkaido University School of Medicine, Sapporo 060-8638, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kojima
authors.forename: Koichi
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Tamura
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Ogura
authors.forename: Kenzaburo
authors.initials: K
authors.lastname: Tani
authors.forename: Jun
authors.initials: J
authors.lastname: Konishi
authors.forename: Naofumi
authors.initials: N
authors.lastname: Shinagawa
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kinoshita
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Hizawa
authors.forename: Etsuro
authors.initials: E
authors.lastname: Yamaguchi
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Dosaka-Akita
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nishimura
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics*; D018845:CD11 Antigens / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D002455:Cell Division; D045744:Cell Line, Tumor; D002465:Cell Movement; D003131:Combined Modality Therapy; D015316:Genetic Therapy; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014161:Transduction, Genetic
chemical_list: D000951:Antigens, Neoplasm; D018845:CD11 Antigens; D019496:Cancer Vaccines; C052646:sarcoma glycoprotein gp96 rejection antigens; D016178:Granulocyte-Macrophage Colony-Stimulating Factor