Activity of IL-12/15/18 primed natural killer cells against hepatocellular carcinoma

Abstract

Background: Hepatocellular carcinoma (HCC) is common, but remains difficult to treat. Natural killer (NK) cells are cells of the innate immune system that have potent anti-cancer activity. Recent work has shown that stimulation with IL-12/15/18 leads to the generation of NK cells with enhanced functional and putative “memory” properties. We have investigated the activity of these NK cells against HCC cell lines in vitro and in a mouse model. Methods: NK cells from healthy donors or individuals with HCC were activated with IL-12/15/18 in vitro and tested for cytotoxic activity against a panel of human HCC cell lines. IL-12/15/18 primed murine NK cells were then infused into a murine model of spontaneously arising HCC to test for anti-tumor activity. Results: NK cells from patients and healthy controls had similar expression levels of activating and inhibitory NK cell receptors. However, proliferation of NK cells from HCC patients was weaker than healthy controls in response to IL-12/15/18 and IL-2 (p < 0.001 at day 9). In vitro, NK cells from both groups of individuals killed HCC targets to similar levels and this was unrelated to NKG2D expression. In a spontaneous model of HCC, IL-12/15/18 activated NK cells trafficked to the liver and resulted in lower levels of spontaneous HCC formation (p < 0.01). Conclusion: Cytokine-primed NK cells from patients with HCC have similar levels of activity against HCC cell lines as those from healthy controls. This type of activated NK cell has immunotherapeutic potential against hepatocellular carcinoma.

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