Ectopically Expressed Membrane-bound Form of IL-9 Exerts Immune-stimulatory Effect on CT26 Colon Carcinoma Cells

Abstract

IL-9 is a known T cell growth factor with pleiotropic immunological functions, especially in parasite infection and colitis. However, its role in tumor growth is controversial. In this study, we generated tumor clones expressing the membrane-bound form of IL-9 (MB-IL-9) and investigated their influences on immune system. MB-IL-9 tumor clones showed reduced tumorigenicity but shortened survival accompanied with severe body weight loss in mice. MB-IL-9 expression on tumor cells had no effect on cell proliferation or major histocompatibility complex class I expression in vitro. MB-IL-9 tumor clones were effective in amplifying CD4+ and CD8+ T cells and increasing cytotoxic activity against CT26 cells in vivo. We also observed a prominent reduction in body weights and survival period of mice injected intraperitoneally with MB-IL-9 clones compared with control groups. Ratios of IL-17 to interferon (IFN)-γ in serum level and tumor mass were higher in mice implanted with MB-IL-9 tumor clones than those observed in mice implanted with control cells. These results indicate that the ectopic expression of the MB-IL-9 on tumor cells exerts an immune-stimulatory effect with toxicity. To exploit its benefits as a tumor vaccine, a strategy to control the toxicity of MB-IL-9 tumor clones should be developed.

Crosstalk between the Producers and Immune Targets of IL-9

“…In psoriasis patients, IL-9R expression was shown to be elevated in samples of lesional skin, and IL-9 treatment increased the number of Th17 cells and hence IL-17 secretion more in peripheral blood mononuclear cells (PBMCs) from psoriasis patients than those from normal healthy controls ( 40 ). In the cancer context, subcutaneous implantation of IL-9 expressing CT26 colon cancer cells clearly showed elevated levels of IL-17 in both blood serum and tumor masses ( 43 ). In this system, although IL-9 definitely reduced colon cancer growth, the survival of mice was not improved.…”

“…Exogenous IL-9 reduced IL-12 and IFN-γ expression from PBMCs leading to negative effects on Th1 polarization ( 15 52 ). The serum level of IFN-γ was significantly elevated in Il9 −/− mice compared with wild type mice ( 15 ) and ectopic implantation of IL-9-expressing tumor cells reduced IFN-γ concentration in both blood and tumor masses ( 43 ). Th2 cells were found to express IL-9R at levels as high as Th17 cells ( 42 ), but there is little evidence for direct effects of IL-9 on Th2 cells.…”

Antibody-based delivery of Interleukin-9 to neovascular structures: therapeutic evaluation in cancer and arthritis

“…However, no substantial differences in tumor growth retardation and body weight change was observed between the treatments with targeted F8IL9F8 and the untargeted variant KSFIL9KSF (based on the irrelevant anti-hen egg lysozyme antibody KSF) ( Figure 3A). The CT26 model, recently described as an immunologically "hot" tumor [40], was investigated due to earlier reports demonstrating in vivo growth impairment of CT26 tumors ectopically expressing IL9 [14,15]. In order to investigate dose dependence effect of IL9 therapy, mice received three injections of F8IL9F8 at different doses, i.e.…”

TH9, TH17, and TH22 Cell Subsets and Their Main Cytokine Products in the Pathogenesis of Colorectal Cancer

“…In vivo , IL-9 overexpression significantly inhibited tumor growth and resulted in a longer survival time in a mouse subcutaneous allograft model (80). Moreover, an ectopically expressed membrane-bound form of IL-9 induces an immunostimulatory effect that suppresses the growth of CT26 colon cancer cells (81). These studies seem to suggest that T H 9 cells have an antitumor effect that largely depends on their ability to secrete IL-9 and may influence tumor growth by enhancing immune responses (73).…”