Exploitation of interleukin-18 by gastric cancers for their growth and evasion of host immunity

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Abstract
Interleukin‐18 (IL‐18) is a pleiotropic cytokine that enhances Th1 or Th2 immune response. We show a novel mechanism of gastric cancer cells that allows their immune escape utilizing IL‐18. All 4 gastric cancer cell lines, but not colon lines, constitutively expressed IL‐18 receptors and IL‐18 dose‐dependently enhanced their in vitro proliferation accompanied by nuclear factor κB activation. When IL‐18‐pretreated gastric cancer cells were cultured with cytokine‐activated peripheral blood killer lymphocytes, the antitumor machineries, perforin or interferon‐γ production of killer lymphocytes decreased, resulting in a decreased susceptibility of cancer cells to killer lymphocytes. Furthermore, gastric cancer cells cultured with IL‐18 showed an increased expression of a granzyme B inhibitor, protease inhibitor 9. IL‐18 injections into severe combined immuno‐deficient mice intraperitoneally inoculated with gastric cancer cells consistently decreased the mouse survival time. Our results indicate that gastric cancers exploit IL‐18 to grow/invade and evade immunosurveillance in the hosts.