title: Interleukin-4 and CpG oligonucleotide therapy suppresses the outgrowth             of tumors by activating tumor-specific Th1-type immune responses.
abstract: Because IL-4 and CpG oligodeoxynucleotides (CpG-ODNs) are immune stimulants, we evaluated the antitumor effects of IL-4 gene therapy and CpG-ODN treatment in a poorly immunogenic murine cancer model. We used a murine colorectal cancer MC38 cell line overexpressing the IL-4 gene (MC38-IL4). Incubation with MC38-IL4 and CpG-ODN enhanced bone marrow-derived dendritic cell (DC) maturation in vitro. In addition, interferon (IFN)-γ production was significantly increased in naïve splenocytes after they were coincubated with MC38-IL4 and CpG-ODN. When mice bearing MC38 wild-type tumors were inoculated subcutaneously with MC38-IL4 cells and CpG-ODN, the outgrowth of established parental tumors was significantly suppressed compared to those in the MC38-IL4-treated group (IL-4 vs. IL-4 + CpG-ODN, p=0.015). A marked infiltration of CD8+ cells in the established parental tumors of mice treated with MC38-IL4 and CpG-ODN was confirmed by immunohistochemical analyses (MC38-IL4, 2.8 ± 1.9 cells/field vs. MC38-IL4 + CpG-ODN, 20.7 ± 15.3 cells/field, p=0.027). Significant tumor-specific cytolysis was detected when splenocytes of MC38-IL4 + CpG-ODN-treated mice were stimulated by γ-irradiated MC38-IL4 cells and CpG-ODN twice weekly in vitro and used as effector cells in a chromium-release assay (32.2 ± 3.5% for MC38 cells vs. 3.2 ± 1.1% for YAC-1 cells; at an effector to target ratio of 40). These results suggest that IL-4 and CpG-ODN treatment promotes potent Th1-type antitumor immune responses. Therefore, the combination of IL-4 gene therapy and CpG-ODN treatment for cancer should be evaluated in clinical trials.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo 142-8666, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kajiwara
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Doi
authors.forename: Junichi
authors.initials: J
authors.lastname: Eguchi
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Ishii
authors.forename: Ayako
authors.initials: A
authors.lastname: Hiraide-Sasagawa
authors.forename: Masashi
authors.initials: M
authors.lastname: Sakaki
authors.forename: Risa
authors.initials: R
authors.lastname: Omori
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Hiroishi
authors.forename: Michio
authors.initials: M
authors.lastname: Imawari
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy; D007371:Interferon-gamma / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics* / Q000276:immunology*; D008223:Lymphoma / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use*; D018417:Th1 Cells / Q000276:immunology*
chemical_list: C423449:CpG ODN 1826; D009838:Oligodeoxyribonucleotides; D015847:Interleukin-4; D007371:Interferon-gamma