title: Antitumor mechanisms of attenuated Salmonella typhimurium containing the gene for human interleukin-2: a novel antitumor agent?
abstract: Currently, there is no long-term effective treatment for unresectable hepatic malignancies. Salmonella species are known to naturally track to the liver during active infection. To develop a biological vector for delivery of interleukin-2 (IL-2) to the liver for antitumor purposes, the thi 4550 attenuated strain of Salmonella typhimurium was used as a vector for IL-2. The gene for human IL-2 was cloned into plasmid pYA292 and inserted into the attenuated S typhimurium and renamed (thi 4550(pIL-2)]. MCA-38 murine adenocarcinoma cells were injected intrasplenically into C57BL/6 mice to produce hepatic metastases that were subsequently enumerated after 12 days. We previously have demonstrated that the thi 4550(pIL-2) produces biologically active IL-2 and that a single gavage feeding of 10(7) thi 4550(pIL-2) significantly reduced the number of hepatic metastases when compared with animals fed salmonella lacking the IL-2 gene or nontreated controls. The aims of the current studies were to determine which host effector cell populations were responsible for the antitumor effect seen with thi 4550(pIL-2) by depletion of natural killer (NK), cytotoxic T lymphocytes (CD8+), T helper (CD4+) cells, and Kupffer cells. Multiple experiments were conducted for each host effector cell population depleted. We found a consistent reduction in the mean number of hepatic metastases in animals fed thi 4550(pIL-2) (55.6 metastases; n = 54) when compared with controls (162.3 metastases; n = 53) (P < .0001). Depletion of NK cells and CD8+ T cells significantly inhibited the antitumor effect of thi 4550(pIL-2) (analysis of variance [ANOVA], P < .01). Elimination of CD4+ T cells and Kupffer cells had no significant impact on the antitumor effect of thi 4550(pIL-2) (ANOVA, P value was not significant). Salmonella IL-2 may represent a novel form of in vivo biotherapy for unresectable hepatic malignancies that employs the oral route of administration. Furthermore, both NK cells or CD8+ cells are required for the antitumor effect seen while CD4+ T cells and Kupffer cells do not appear to be as essential.
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis 55455, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Saltzman
authors.forename: E
authors.initials: E
authors.lastname: Katsanis
authors.forename: C P
authors.initials: CP
authors.lastname: Heise
authors.forename: D E
authors.initials: DE
authors.lastname: Hasz
authors.forename: V
authors.initials: V
authors.lastname: Vigdorovich
authors.forename: S M
authors.initials: SM
authors.lastname: Kelly
authors.forename: R
authors.initials: R
authors.lastname: Curtiss
authors.forename: A S
authors.initials: AS
authors.lastname: Leonard
authors.forename: P M
authors.initials: PM
authors.lastname: Anderson
mesh_terms: D018195:Adenosarcoma / Q000276:immunology / Q000473:pathology / Q000556:secondary* / Q000628:therapy*; D000704:Analysis of Variance; D000818:Animals; D005822:Genetic Vectors; D007376:Interleukin-2 / Q000235:genetics / Q000627:therapeutic use*; D007694:Killer Cells, Natural; D007728:Kupffer Cells; D008099:Liver / Q000276:immunology / Q000473:pathology; D008113:Liver Neoplasms / Q000276:immunology / Q000473:pathology / Q000556:secondary* / Q000628:therapy*; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D012486:Salmonella typhimurium; D013602:T-Lymphocytes, Cytotoxic; D006377:T-Lymphocytes, Helper-Inducer
chemical_list: D007376:Interleukin-2